AU752531B2 - Multiple target hybridizing nucleic acids, their preparation, compositions, formulation, kits and applications - Google Patents

Description

WO 99/13886 PCT/US98/19419 MULTIPLE TARGET HYBRIDIZING NUCLEIC ACIDS, THEIR PREPARATION, COMPOSITIONS, FORMULATION, KITS APPLICATIONS BACKGROUND OF THE INVENTION Field of the Invention This invention relates to multiple target anti-sense oligonucleotides (MTA oligos) of low or no adenosine content. The present agents are effective in the prophylaxis and treatment of diseases and conditions associated with inflammation, impaired airways, including lung disease and diseases whose secondary effects afflict the lungs of a subject. The agents are targeted to specific genes, genomic flanking regions, initiation codon, intron-exon borders, and the like, or the coding and non-coding regions of RNAs, including those encoding certain proteins, particularly those associated with diseases having multiple mediators, by affecting (either attenuating or enhancing) various contributing pathways. Examples are pulmonary diseases such as allergies, asthma, impeded respiration, pain, cystic fibrosis and cancers such as leukemias, e.g. colon cancer, and the like. The present agent may easily be administered prophylactically and therapeutically in conjunction with other therapies, or may be utilized as a substitute for therapies that have significant, negative side effects.

Description of the Background Respiratory ailments, associated with a variety of diseases and conditions, are extremely common in the general population, and more so in certain ethnic groups, such as African Americans. In some cases they are accompanied by inflammation, which aggravates the condition of the lungs. Asthma, for example, is one of the most common diseases in industrialized countries. In the United States it accounts for about 1% of all health care costs.

An alarming increase in both the prevalence and mortality of asthma over the past decade has been reported, and asthma is predicted to be the preeminent occupational lung disease in the next decade. While the increasing mortality of asthma in industrialized countries could be attributable to the increased reliance upon beta agonists in the treatment of this disease, the underlying causes of asthma remain poorly understood.

Anti-sense oligonucleotides have received considerable theoretical consideration as potential useful pharmacological agents. in human disease. Their practical. application in actual models of human disease, however, has been somewhat elusive. One important impediment to their effective application has been a difficulty in finding an appropriate route of administration to deliver them to their site of action. Many in vivo experiments were conducted by administering anti-sense oligonucleotides directly to specific regions of the brain. These applications, however, necessarily have limited clinical utility due to their invasive nature.

The systemic administration of anti-sense, oligonucleotides also presents significant problems, -not the least being an inherent difficulty in targeting disease-involved tissues. In WO 99/13886 PCT/US98/19419 contrast, the lung is an excellent target for the direct administration of anti-sense oligonucleotides, and provides a non-invasive and a tissue-specific route. The delivery of antisense agents to the lung has been relatively undeveloped.

Adenosine may constitute an important mediator in the lung for various diseases, including bronchial asthma. Its potential role was suggested by the finding that asthmatics respond favorably to aerosolized adenosine with marked bronchoconstriction whereas normal individuals do not. An asthmatic rabbit animal model, the dust mite allergic rabbit model for human asthma, responded in a similar fashion to aerosolized adenosine with marked bronchoconstriction whereas non-asthmatic rabbits showed no response. More recent work with this animal model suggested that adenosine-induced bronchoconstriction and bronchial hyperresponsiveness in asthma may be mediated primarily through the stimulation of adenosine receptors. Adenosine has also been shown to cause adverse effects, including death, when administered therapeutically for other diseases and conditions in subjects with previously undiagnosed hyper reactive airways.

A handful of medicaments have been available for the treatment of respiratory diseases and conditions, although in general they all have limitations. Theophylline, an important drug in the treatment of asthma, is a known adenosine receptor antagonist which was reported to eliminate adenosine-mediated bronchoconstriction in asthmatic rabbits. A selective adenosine A, receptor antagonist, 8-cyclopentyl-l, 3-dipropylxanthine (DPCPX) was also reported to inhibit adenosine-mediated bronchoconstriction and bronchial hyperresponsiveness in allergic rabbits. The therapeutic and preventative applications of currently available adenosine A, receptor-specific antagonists are, nevertheless, limited by their toxicity. Theophylline, for example, has been widely used in the treatment of asthma, but is associated with frequent, significant toxicity resulting from its narrow therapeutic dose range. DPCPX is far too toxic to be useful clinically. The fact that, despite decades of extensive research, no specific adenosine receptor antagonist is available for clinical use attests to the general toxicity of these agents.

Anti-sense oligonucleotides have received considerable theoretical consideration for their potential use as pharmacological agents in human disease. Finding practical and effective applications of these agents in actual models of human disease, however, have been few and far between, particularly because they had to be administered in large doses. Another important consideration in the pharmacologic application of these molecules is their route of administration. Many in vivo applications have involved the direct administration of anti-sense oligonucleotides to limited regions of the brain. Such applications, however, have limited clinical utility due to their invasive nature.

The,systemic administration of anti-sense oligonucleotides as pharmacological agents .2 WO 99/13886 PCT/US98/19419 has been found to have also significant problems, not the least of which being a difficulty in targeting disease-involved tissues. That is, the necessary dilution of the anti-sense oligonucleotide in the circulatory system makes extremely difficult to attain a therapeutic dose at the target tissue by intravenous or oral administration. The bioavailability of orally administered anti-sense oligonucleotides is very low, of the order of less than about Anti-sense oligonucleotides have been used in therapy by many, including the present inventor, who in his previous work successfully treated various diseases and conditions by direct administration of these agents to the lung. In many instances, other workers have had to face the difficulties associated with the delivery of DNA molecules to a desired target. Thus, the route of administration may be of extreme importance for treating generalized diseases and conditions as well as those which are localized.

Accordingly, there is a need for effective ways to implement anti-sense therapy, particularly those which are highly effective for the treatment or diseases and conditions which are of a complex nature. Examples of the latter are those diseases and conditions which are associated with complex pathways and multiple endogenous agents which either alone, or in combination with one another, result in pathological conditions to the subject.

SUMMARY OF THE INVENTION This invention relates to an agent, comprising an anti-sense oligonucleotide hybridizing to two or more mRNAs, or multiple target anti-sense oligos (MTA oligos), such as those that correspond to target genes, genomic flanking regions, the initiation codon, intron-exon borders, and the like, and the entire sequence of RNAs, including the coding region of mRNA and non-coding RNA segments such as the 5' cap or end and the 3' end, e.g. poly-A segment, and RNAs encoding proteins known to be associated with one or more diseases or conditions and mixtures thereof. The mRNAs, for example, may encode polypeptide(s) such as transcription factors, stimulating and activating factors, interleukins, interleukin receptors, chemokines, chemokine receptors, endogenously produced specific and non-specific enzymes, immunoglobulins, antibody receptors, central nervous system (CNS) and peripheral nervous and non-nervous system receptors, CNS and peripheral nervous and non-nervous system peptide transmitters, adhesion molecules, defensines, growth factors, vasoactive peptides and receptors, and binding proteins; or those mRNA which correspond to an oncogene. The present agent contains less than or about 15% adenosine and in many cases is completely devoid of adenosine, and is also presented as a composition, which may be in the form of a capsule or cartridge, various formulations, and a kit provided with a delivery device and instructions for its use. The anti-sense-oligos of the invention may have their adenosine content reduced by'stibstitution with an adenosine-like binding substitute such as universal base.

WO 99/13886 PCT/US98/19419 The kit may also have other therapeutic agents, and ingredients for the composition. The agent also may be provided operatively linked to a vector and/or in a transfected host cell.

The agent, composition and formulation of the invention may be applied to the treatment of a disease or condition associated with the presence of an mRNA corresponding to at least one target gene, genomic flanking regions or proteins, by administration to a subject afflicted with the disease or condition of an amount of the MTA oligo of this invention effective to reduce the production or availability, or to increase the degradation, by the subject of at least one of the target mRNA. In a preferred embodiment, the agent may be administered in an amount effective to reduce the production or availability, or to increase the degradation of at least two of the target mRNAs. Typical diseases and conditions of this invention are those associated with impaired respiration and inflammation, including lung diseases, ailments and conditions that have a negative effect on the lungs of a subject. Examples of diseases and conditions, which may be treated preventively, prophylactically and therapeutically with the agent of this invention, are pulmonary vasoconstriction, inflammation, allergic rhinitis, acute asthma, allergies, asthma, impeded respiration, respiratory distress syndrome, pain, cystic fibrosis, pulmonary hypertension, pulmonary vasoconstriction, emphysema, chronic obstructive pulmonary disease (COPD), and cancers such as leukemias, lymphomas, carcinomas, and the like, e.g. colon cancer, breast cancer, lung cancer, pancreatic cancer, hepatocellular carcinoma, kidney cancer, melanoma, hepatic metastases, etc., as well as all types of cancers which may metastasize or have metastasized to the lung(s), including breast and prostate cancer. The present agent(s) is (are) also suitable for administration before, during and after other treatments, including radiation, chemotherapy, antibody therapy, phototherapy and cancer, and other types of surgery. Alternatively, the present agent may be effectively administered preventively, prophylactically or therapeutically, and in conjunction with other therapies, or by itself for conditions without known therapies or as a substitute for therapies that have significant negative side effects.

The composition of this invention may be administered by transdermal or systemic routes, including by, but not exclusively, oral, intracavitary, intranasal, intraanal, intravaginal, transdermal, intradermal, intrabuccal, intravenous, subcutaneous, intramuscular, intratumor, intraglandular, by inhalation, intraarterial, intravascular in general, into the ear, intracranial, intrathecal, intraorgan including via a shunt to, for example, the liver or other organs, by implantation and intraocular administration to a human or any other animal, including vertebrates, such as mammals. The treatment of this invention may be prophylactic or therapeutic.. In a preferred embodiment, the present agents are administered directly into the respiratory system of a subject, so that the agent has direct access to the lungs, in an amount effective to reduce or inhibit the effect in the lung of the targeted diseases or conditions.

4 i 4 5 The agent of this invention may be produced by selecting two or more targets such as genes, gencinic flanking regions, intronexon borders, and the like, or the entire sequence of RNAs, including non-coding RNAs, and RNAs, encoding proteins known to be associated with at least one disease or condition; obtaining RNAs selected fran the group consisting of RNAs corresponding to the genes and genomic flanking regions, and RNAs encoding the target proteins; selecting a segment of a first RNA which is at least about preferably about 80%, and still more preferably about 90% and even about 100% homologous to a segment of at least a segment of a second RNA; and synthesizing one or more anti-sense oligcnucleotide(s) to the one or more RNA segments. The target RNA includes every segment of precursor and spliced mRNAs and other RNA molecules, including the and 3 -ends, and the coding portions as well as overlapping segments juxtaposed over the coding and noncoding sequences. In a preferred form of the invention, the two or more targets may be located in the same molecule. For instance, in the case of a mRNA encoding a protein with multiple subunits, MRA oligos may be found in segments of the RNA which encode different protein subunits.

Also provided are MTA oligos which are produced by the method of the invention.

S"Throughout the description and claims of this specification, the word -ccmprise" and variations of the word, such 25 as "comprising- and "comprises", means "including but not limited to", and is not intended to exclude other additives, components, integers or steps".

It will be clearly understood that, although a rnmber of prior art publications are referred to herein, this reference does 30 not constitute an admission that any of these documents forms part eve.

of the ccmmn general knowledge in the art, in Australia or in any other country.

DETALED DESCRIPTICN OF THE PREFERRED EMBODIMENTS This invention arose frum a desire by the inventor to improve on his own prior discovery, and those of others, that anti-sense _oligonucleotides may be utilized therapeutically in the treatment of H:\Bkrot\Keep\speci\93951-98.doc 22/09/00 5a diseases or conditions which have multiple contributing pathways.

The inventor reasoned that he could improve on his prior success in attenuating or enhancing the effects of one specific pathway by designing anti-sense oligonumcleotides directed to a specific target associated with a disease or condition. He, thus, set out to attempt a novel and unobvious strategy directed to multiple targets.

In so doing, he overcame nmerous obstacles, particularly the extensive searching and selection necessary to obtain targets as well as their locating the desired sequences, be it gencmic ENA, RNAs or proteins involved in specific diseases. Thereafter, he exiemplified the invention by application to some specific diseases or conditions, and provided various preferred embodiments and specifically designed multiple targeted anti-sense oligonucleotide (MTA oligo) sequences.

The multi-targeted anti-sense (MTA) oligonucleotides of this invention have the capacity to attenuate the expression of more. than one target mRNA, or to enhance or attenuate the activity of one or more pathways. By means of example, the present method may be practiced by first identifying all possible desadenosine (desA) anti-sense sequences of about 7, about 10, about 12, about 15, about 18, about 21 to about 28, about 30, about 35, about 40, about about 50, about 60 or more moncnucleotides in a target mRNA. This may be attained by searching for segments that are 7 or more g* lnc nucleotides long within a target sequence.

0

S

S

S So*

S

°SS°

fgt H:\Bkrot\Keep\speci\93951-98.doc 22/09/00 WO 99/13886 PCT/US98/19419 which are low in, or lack, thymidine a nucleotide which is complementary to adenosine This search typically results in about 10 to 30 such desT segments, i. e. naturally lacking thymidine, or segments with low T content, e. g. up to and including about 15%T, from which anti-sense oligonucleotides of varying lengths may be designed for a typical target mRNA of average length, i. e. about 1800 nucleotides long. Thereafter, the sense sequence for each strictly complementary desA anti-sense sequence obtained for a specific target may be then deduced. The thus deduced sense sequence may be then used to search for sequences of preferred secondary targets. Alternatively, one or more sequence data bases, e. g., GENBANK, and the like, may be searched for alternative secondary sequences.Thus, the targeting may be undertaken in several manners, one being the selection of specific targets associated with one or more related diseases. Alternatively, a primary target may be selected first, and an anti-sense oligonucleotide found, preferably a desA oligonucleotide and, then, secondary, tertiary or more targets searched for. In a typical search, either the list of preferred secondary targets or of a data base, multiple instances of homologous secondary targets of interest are identified. That is, the present technology is directed to finding the instances where there are natural homologies between primary, secondary, and greater sequences, and utilizing the finding for the therapeutic treatment of specific diseases or conditions associated with the target macromolecules from which the MTAs are obtained.

The present technology relies on the design of anti-sense oligos targeted to mRNAs associated with ailments involving lung airway pathology(ies), and on their modification to reduce the occurrence of undesirable side effects caused by their release of adenosine upon breakdown, while preserving their activity and efficacy for their intended purpose. In this manner, the inventor targets a specific gene to design one or more anti-sense oligonucleotide(s) (oligos) that selectively bind(s) to the corresponding mRNA, and then reduces, if necessary, their content of adenosine via substitution with universal base or an adenosine analog incapable of activating adenosine A, A 2 b or A 3 receptors. Based on his prior experience in the field, the inventor reasoned that in addition to "downregulating" specific genes, he could increase the effect of the agent(s) administered by either selecting segments of RNA that are devoid, or have a low content, of thymidine or, alternatively, substitute one or more adenosine(s) present in the designed oligonucleotide(s) with other nucleotide bases, so called universal bases, which bind to thymidine but lack the ability to activate adenosine receptors and otherwise exercise the constricting effect of adenosine in the lungs, etc. Given that adenosine is a nucleotide base complementary to thymidine when a T appears in the RNA, the anti-sense oligo will have an A at the same position. For consistency's sake, all RNAs and oligonucleotides are represented in this patent by a single strand in the 5' to 3' direction, when read from left.to right, although their complementary sequence(s) is (are) also encompassed 6, WO 99/13886 PCT/US98/19419 within the four corners of the invention. In addition, all nucleotide bases and amino acids are represented utilizing the recommendations of the IUPAC-IUB Biochemical Nomenclature Commission, or by the known 3-letter code (for amino acids).

The method of the present invention may be used to treat ailments associated with reduced airway function in a subject, whatever its cause. The adenosine content of the antisense agent(s) of the invention have a reduced A content to prevent its liberation upon in vivo degradation of the agent(s). Examples of airway diseases that may be treated by the method of the present invention include cystic fibrosis, asthma, pulmonary hypertension and vasoconstriction, chronic obstructive pulmonary disease (COPD), chronic bronchitis, respiratory distress syndrome, lung cancer and lung metastatic cancers and other airway diseases, including those with inflammatory response.

Anti-sense oligos to the adenosine A 1

A

2 h, A 2 b, and A 3 receptors, CCR3 (chemokine receptors), bradykinin 2B, CAM (vascular cell adhesion molecule), and eosinophil receptors, among others, have been shown to be effective in down-regulating the expression of their genes. Some of these act to alleviate the symptoms or reduce respiratory ailments and/or inflammation, for example, by "down regulation" of the adenosine A 2

A

2 b, and/or A 3 receptors and CCR3, bradykinin 2B, VCAM (vascular cell adhesion molecule) and eosinophil receptors. These agents are preferably administered directly into the respiratory system, e.g., by inhalation or other means, so that they may reach the lungs without widespread systemic dissemination. This permits the use of substantially lower doses of the agent of the invention as compared with those administered by the prior art, systemically or by other generalized routes and, consequently, reduce undesirable side effects resulting from the agent's widespread distribution in the body. The agent(s) of this invention has (have) been shown to reduce the amount of receptor protein expressed by the tissue. These agents, thus, rather than merely interacting with their targets, e.g. a receptor, lower the number of target proteins that other drugs may interact with. In this manner, the present agent(s) afford(s) extremely high efficacy with low toxicity.

The adenosine receptors discussed above are mere examples of the high power of the inventor's technology. In fact, a large number of genes may be targeted in a similar manner by the present agent(s), to reduce or down-regulate protein expression. By means of example, if the target disease or condition is one associated with impeded or reduced breathing, bronchoconstriction, chronic bronchitis, pulmonary bronchoconstriction and/or hypertension, chronic obstructive pulmonary disease (COPD), allergy, asthma, cystic fibrosis, respiratory distress syndrome, cancers, which either directly or by metastasis afflict the lung, the present method may be applied to a list of potential target mRNAs, which includes the targets listed in Table 1 below, among others.

7 WO, 99/13886 PCT/1JS98/19419 Tabl Pulmonary Disease or Condition (Asthma/Inflamnmation) Targets NfKB Transcription Factor Receptor (IL-5R) Interleukin-3 Receptor (IL-3R) lnterleukin-ip Receptor (IL-l0R) Tryptase P2-adrenergic Receptor Kinase Endothelin Receptor B Bradykinin B2 Receptor (B2BR) Interleukin- 1 (IL-i) Jnterleukin-9 (IL-9) Interleukin-1 1 (IL-il1) Inducible Nitric Oxide Synthase Intracellular Adhesion Molecule I (F Rantes Cyclooxygenase-2 (COX-2) Monocyte Activating Factor Neutrophil Elastase Muscarinic Acetylcholine Receptors Tumor Necrosis Factor a Phosphodiesterase IV Substance P Receptor Chymase Interleukin-2 (IL-2) Interleukin- 12 (IL- 12) lnterleukin-6 (IL-6) Interleukin-8 (IL-8) Interleukin-7 Receptor (IL-7R) Interleukin-14 Receptor (IL-14R) CCR-2 CC Chemokine Receptor CCR-4 CC Chemokine Receptor Prostanoid Receptors Neutrophil Adherence Receptor Interleukin-i5 (IL-15) Interleukin- 11 (IL-l11) NFAT Transcription Factors Interleukin-8 Receptor (Iti8 R) Interleukin-4 Receptor (1L-4R1) Interleukin- I P (IL-1 P3) Eotaxin Major Basic Protein Endothelin Receptor A Preproendothelin IgE (High Affinity Receptor) Interleukin 1 Receptor (IL-i R) Interleukin-9 Receptor (IL-9 R) Interleukin- 11I Receptor (IL-II R) Cyclooxygenase (COX) CAM-i) Vascular Cellular Adhesion Molecule (VCAM) Endothelial Leukocyte Adhesion Molecule (ELAM- 1) GM-CSF, Endothelin-1 Neutrophil Chemnotactic Factor Defensin 1,2,3 Platelet Activating Factor Substance P Histamine Receptor CCR- 1 CC Chemokine Receptor lnterleukin-4 (IL-4) Interleukin-5 Interleukin-7 (IL-7) Interleukin-i2 Receptor (IL-12R) Interleukin-I (IL-I) Interleukin- 14 CCR-3 CC Chemokine Receptor CCR-5 CC Chemokine Receptor GATA-3 Transcription Factor MAP Kinase Interleukin-15 Receptor lnterleukin-l 1 Receptor (IL- II R) STAT 4 ~1.

WO 99/13886 WO 9913886PCT/US98/1 9419 Ta-ble I: Pulmonary Disease or Condition (Asthina/Inflammation) Targets (Cont'ed) MCP-3 Cyclophillin B, etc.) Basic Fibroblast Growth Factor CSBP/p38 MAP Kinase PDG2 Interleukin- 10 (IL-lO) FK506-Binding Protein Fibronectin cMad CAM-i PECAM- 1 C3bi E-Selectin CD-34 p 150,95 Fucosyl transferase CD- 18/CD11a ICAM2 and ICAM3 CCR3 (Eptaxin Receptor) LTB-4 Protein kinase C Tachykinnen Receptors (tach R) Interleukin-2 Receptor (IL-2R) STAT 6 NF-Interleukin-6 (NF-IL-6) Interleukin-3 (IL-3) Interleukin-13 (IL-13) Interleukin-14 (IL-14) Interleukin-16 (IL-16) Medullasin Adenosine A, Receptor R) Adenosine A 2 Receptor (Ab R) P3 Tryptase Adenosine A 2 Receptor (A 2

R)

Fc-epsilon receptor CD23 antigen IgE Receptor Fc Epsilon Receptor (IgERFc Histidine decarboxylase Prostaglandin D Synthase Eosinophil Derived Neurotoxin Endothelial Nitric Oxide Synthase Neutrophil Oxidase Factor Macrophage Inflammatory Protein-i- Alpha/Rantes Receptor Endothelin Receptor ET-B MCP-2 Phospholipase A2 Metalloproteinase Tryptase Receptor lnterleulcin-3 (IL-3) Cyclosporin A Binding Protein a4PI1 Selectin a4P7 Selectin LFA-1I (CD IIa/CD 18) LFA-1 Selectin PSGL- 1 P-Selectin L-Selectin Mac-i (CD11b/CDL8) VLA-4 CD1 lb/CD18 CCR1, CCR2, CCR4, AP- I Transcription Factor Cysteinyl Leukotriene Receptor IKB Kinase 1 2 Substance P, NK-1 NK-3 Receptors) c-mas Interleukin-10 Receptor (IL-lOR) Interleukin-2 Receptor (IL-2R) Interleukin-12 Receptor (IL-12R) Interleukin-6 Receptor (IL-6R) Interleukin-13 Receptor (IL-13R) Interleukin-16 Receptor (IL-16R) Tryptase-I Adenosine A 3 Receptor (A 3

R)

IgE Receptor P3 Subunit (IgE R Pi) IgE Receptor a Subunit (IgE R a) R) Substance P Receptor Tryptase- 1 Eosinophil Cationic: Protein Eosinophil Peroxidase Endothelial Monocyte Activating Factor Cathepsin G Interleukin-8 Receptor a Subunit (IL-8 R a) Substance P Endothelin ETA Receptor The oligos of this invention may be obtained by first selecting fragments of a target nucleic acid having at least 4 contiguous nucleic acids selected from the group consisting of G and C, and then obtaining a first oligonucleotide 4 to 60 nucleotides- long which comprises the selected fragment and has a C and G nucleic acid content of up to and including about The latter step may be conducted by obtaining a second oligonucleotide 4 to nucleotides long comprising a sequence which is anti-sense to the selected fragment, the second oligonucleotide having an adenosine base content of up to and including about 15 This method may~also comprise, when the selected fragment comprises at least one thyniidine base, WO 99/13886 PCT/US98/19419 substituting an adenosine base in the corresponding nucleotide of the anti-sense fragment with a universal base selected from the group consisting of heteroaromatic bases which bind to a thymidine base but have antagonist activity and less than about 0.3 of the adenosine base agonist activity at the adenosine A 2 b and A 3 receptors, and heteroaromatic bases which have no activity or have an agonist activity at the adenosine A2a receptor. The analogue heteroaromatic bases may be selected from all pyrimidines and purines, which may be substituted by 0, halo, NH2, SH, SO, SO 2

SO

3 COOH and branched and fused primary and secondary amino, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, alkenoxy, acyl, cycloacyl, arylacyl, alkynoxy, cycloalkoxy, aroyl, arylthio, arylsulfoxyl, halocycloalkyl, alkylcycloalkyl, alkenylcycloalkyl, alkynylcycloalkyl, haloaryl, alkylaryl, alkenylaryl, alkynylaryl, arylalkyl, arylalkenyl, arylalkynyl, arylcycloalkyl, which may be further substituted by 0, halo, NH2, primary, secondary and tertiary amine, SH, SO,

SO

2

SO

3 cycloalkyl, heterocycloalkyl and heteroaryl. The pyrimidines and purines may be substituted at all positions as is known in the art, but preferred are those which are substituted at positions 1, 2, 3, 4, 7 and/or 8. More preferred are pyrimidines and purines such as theophylline, caffeine, dyphylline, etophylline, acephylline piperazine, bamifylline, enprofylline and xantine having the chemical formula 0 N II I C N wherein R' and R 2 are independently H, alkyl, alkenyl or alkynyl and R 3 is H, aryl, dicycloalkyl, dicycloalkenyl, dicycloalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, 0cycloalkyl, O-cycloalkenyl, O-cycloalkynyl, NH 2 -alkylamino-ketoxyalkyloxy-aryl, mono and dialkylaminoalkyl-N-alkylamino-SO 2 aryl, among others.

When no segments having the desired T content were found or where desirable segments contained T, the inventor proposed to reduce the adenosine content of the anti-sense oligos corresponding to the thymidines present in the target RNA to less than about or fully eliminated A from the oligonucleotide sequence as a means for preventing their breakdown products from freeing adenosine into the lung tissue environment and, thereby, aggravating the subject's ailment and/or countering the beneficial effect of the administered agent.

By means of example, the NfKB transcription factor may be selected as a primary target and searched for desthymidine (desT) segments. When a number of desT segments are found, WO 99/13886 PCT/US98/19419 the anti-sense segments may be deduced, and perhaps about 20 or even more desA anti-sense sequences obtained. These anti-sense sequences represent, when possible, all desA anti-sense sequences found within the mRNA of this primary target, and may be utilized to start the search for homologous sequences within a preferred list of secondary targets such as the one shown in Table 1 above or Table 2 below, or within a sequence data base, such as GENBANK.

For each of the about 20 original desA anti-sense sequences found for NFKic transcription factor, typically about 10 to 30 homologous sequences may be found among the other members of the group shown in Table 1 above (secondary, tertiary, and the like targets). In some instances, the search produces a homology for the primary target with, not only secondary targets (homology between primary target and sequence from one other target mRNA), but with tertiary targets (homology between primary target and sequences from, e. g. three other target mRNA), as well. The latter case, however, is more rare. When this occurs, the anti-sense oligos found are said to be 100% homologous. More typically, however, the sequences found contain some non-fully homologous nucleotides within the secondary or tertiary or quaternary sequences. In many cases, this mismatch would suffice to render the anti-sense oligonucleotide less active or even inactive against the target(s). In some instances, the presence of even one non-homologous nucleotide may be sufficient to reduce the activity of an anti-sense oligonucleotide. When the so called "homologous" sequences obtained have mismatches, acceptable are up to about 40%, preferably no more than about 30%, more preferable no more than 20%, still more preferable no more than 10% mismatched nucleotides. In some instances the higher mismatches are acceptable, and the oligos still are active since the nonhomologous nucleotide may be "fixed" or replaced with a "Universal" base that may base-pair with similar or equal affinity with two or more of the four nucleotide present in natural DNA: A, G, C, and T. This "fixing" step generates a further novel sequence, different from the one found in nature, that permits the anti-sense oligonucleotide to bind, preferably equally well, with the primary target, the secondary target, the tertiary target, etc.

As the NfKB transcription factor is selected as a target, its mRNA or DNA are searched for low thymidine or desthymidine (desT) fragments. Only desT segments of the mRNA or DNA are selected which, in turn, will produce desA anti-sense as their complementary strand. When a number of RNA desT segments are found, the sequence of the anti-sense segments may be deduced. Typically, about 10 to 30 and even larger numbers of desA antisense sequences may be obtained. These anti-sense sequences may include some or all desA anti-sense oligonucleotide sequences corresponding to desT segments of the mRNA of the target, such as anyone of those shown in Table 1 above or Table 2 below. When this occurs, the anti-sense oligonucleotides found are said to be 100% A-free. For each of the original desA anti-sense oligonucleotide sequences corresponding to the target gene, e.g. the NFKB 11 WO 99/13886 PCT/US98/19419 transcription factor, typically about 10 to 30 sequences may be found within the target gene or RNA which have a low content of thymidine (RNA). In accordance with this invention, the selected fragment sequences may also contain a small number of thymidine (RNA) nucleotides within the secondary or tertiary or quaternary sequences. In some cases, a large adenosine content may suffice to render the anti-sense oligonucleotide less active or even inactive against the target. In accordance with this invention, these so called "non-fully desA" sequences may preferably have a content of adenosine of less than about 15%, more preferably less than about and still more preferably less than and some even less than 2% adenosine. In some instances a higher content of adenosine is acceptable and the oligonucleotides are still active, particularly where the adenosine nucleotide may be "fixed" or replaced with a "Universal" base that may base-pair with similar or equal affinity to two or more of the four nucleotide present in natural DNA: A, G, C, and T. A universal base is defined in this patent as any compound, more commonly an adenosine analogue, having the capacity to hybridize to thymidine, preferably having substantially reduced, or substantially lacking, ability to bind adenosine receptors. Alternatively, adenosine analogs which do not activate adenosine receptors, such as the adenosine A2 h and/or A 3 receptors, most preferably A, receptors, may be used. One example of a universal base is a-deoxyribofuranosol-(5-nitroindole), and an artisan will know how to select others. This "fixing" step generates a further novel sequence, different from the one found in nature, that permits the anti-sense oligonucleotide to bind, preferably equally well, with the target RNA. An example of a universal base is 2- Other examples of universal bases are 3 -nitropyrrole-2'deoxynucleoside, 5-nitro-indole, 2-deoxyribosyl-(5-nitroindole), nitroindole), 2'-deoxyinosine, 2'-deoxynebularine, 6H, 8H-3,4-dihydropyrimido oxazine-7-one and 2 -amino-6-methoxyaminopurine. In addition to the above, Universal bases which may be substituted for any other base although with somewhat reduced hybridization potential, include 3-nitropyrrole 2'-deoxynucleoside 2'-deoxyinosine and 2'-deoxynebularine (Glen Research, Sterling, VA). More specific mismatch repairs may be made using nucleotide, 6H, 8H-3, 4-dihydropyrimido[4,5-c] oxazin-7-one, which base pairs with either guanine or adenine and "K" nucleotide, 2 -amino-6-methoxyaminopurine, which base pairs with either cytidine or thymidine among others. Others which are known in the art are also suitable. See, for example, Loakes, D. and Brown, D. Nucl .Acids Res. 22:4039-4043 (1994); Ohtsuka, E. et al., J. Biol. Chem.260(5):2605-2608 (1985); Lin, P.K.T. and Brown, D. Nucleic Acids Res. 20(19):5149-5152 (1992; Nichols, R. et al., Nature 369(6480): 492-493 (1994); Rahmon M. S. and Humayun, N. Mutation Research 377 263-8 (1997); Amosova, et al., Nucleic Acids Res. 25 1930-1934 (1997); Loakes D. Brown, D. Nucleic i, WO 99/13886 PCT/US98/19419 Acids Res. 22 4039-4043 (1994), the entire sections relating to universal bases and their preparation and use in nucleic acid binding is inceorporated herein by reference.

When non-fully desT sequences are found in the naturally occurring target, they typically are selected so that about 1 to 3 universal base substitutions will suffice to obtain a 100% "desA" anti-sense oligonucleotide. Thus, the present method provides either anti-sense oligonucleotides to different targets which are low in, or devoid of, A content, as well as antisense oligonucleotides where one or more adenosine nucleotides, e. g. about 1 to 3, or more, may be "fixed" by replacement with a "Universal" base. Universal bases are known in the art and need not be listed herein. An artisan will know which bases may act as universal bases, and replace them for A.

The present approach to the design of anti-sense oligonucleotide approach is also applicable to a variety of other diseases or conditions, including other inflammatory diseases, such as cystic fibrosis, chronic obstructive pulmonary disease, chronic bronchitis, pulmonary hypertension, cancers, including those which metastasize to the lung, such as breast cancer, colon cancer, respiratory distress syndrome, prostate cancer, pancreatic cancer, kidney cancer, lymphomas, melanomas, hepatocellular carcinomas, etc.

As used herein, the term "treat" or "treating" asthma or other respiratory and inflammatory conditions or diseases refers to a treatment which decreases the likelihood that the subject administered such treatment will manifest symptoms of a respiratory or inflammatory lung disease or other lung conditions. The term "down-regulate" refers to inducing a decrease in production, secretion or availability (and thus a decrease in concentration) of the targeted intracellular protein.

The present invention is concerned primarily with the treatment of vertebrates, and within this group, of mammals, including human and non-human simians, wild and domesticated animals, marine and land animals, household pets, and zoo animals, for example, felines, canines, equines, pachiderms, cetaceans, and still more preferably to human subjects.

One particularly suitable application of this technology is for veterinary purposes, and includes all types of small and large animals in the care of a veterinarian, including wild animals, marine animals, household animals, zoo animals, and the like. Targeted genes and proteins are preferably mammalian, and the sequences targeted are preferably of the same species as the subject being treated. Although in many instances, targets of a different species are also suitable, particularly those segments of the target RNA or gene that display greater than about homology, preferably greater than about 85 homology, still more preferably greater than about 95 homology, with the recipient's sequence. A preferable group of agents is composed of des-A anti-sense oligos. Another preferred group is composed of non-fully desA oligonucleotides, where one or more adenosine bases are replaced with universal bases.

i13- WO 99/13886 PCT/US98/19419 The terms "anti-sense" oligonucleotides generally refers to small, synthetic oligonucleotides, resembling single-stranded DNA, which in this patent are applied to the inhibition of gene expression by inhibition of a target messenger RNA (mRNA). See, Milligan, J. F. et al., J. Med. Chem. 36(14), 1923-1937 (1993), the relevant portion of which is hereby incorporated in its entirety by reference. The present agents inhibit gene expression of target genes, such as those of the adenosine A, A 2 a, A 2 b, or A 3 receptors, CCR3 (chemical receptor 320, also known as the eotaxin receptor), VCAM (vascular cell adhesion molecule), eonophil receptor, bradykinin 2B receptor, and many others listed in Table 1 above. This is generally attained by hybridization of the anti-sense oligonucleotides to coding (sense) sequences of a targeted messenger RNA (mRNA), as is known in the art. The exogenously administered agents of the invention decrease the levels of mRNA and protein encoded by the target gene and/or cause changes in the growth characteristics or shapes of the thus treated cells. See, Milligan et al. (1993); Helene, C. and Toulme, J. Biochim. Biophys. Acta 1049, 99-125 (1990); Cohen, J. S. Ed., Oligodeoxynucleotides as Anti-sense Inhibitors of Gene Expression; CRC Press: Boca Raton, FL (1987), the relevant portion of which is hereby incorporated in its entirety by reference. As used herein, "anti-sense oligonucleotide" is generally a short sequence of synthetic nucleotide that hybridizes to any segment of a mRNA encoding a targeted protein under appropriate hybridization conditions, and which (2) upon hybridization causes a decrease in gene expression of the targeted protein.

The terms "des-adenosine" (desA) and "des-thymidine" (desT) refer to oligonucleotides substantially lacking either adenosine (desA) or thymidine (desT). In some instances, the des T sequences are naturally occurring, and in others they may result from substitution of an undesirable nucleotide by another one lacking its undesirable activity. In the present context, the substitution is generally accomplished by substitution of A with a "universal base", as is known in the art.

The mRNA sequence of the targeted protein may be derived from the nucleotide sequence of the gene expressing the protein. For example, the sequence of the genomic human adenosine A, receptor and that of the rat and human adenosine A 3 receptors are known. See, US Pat. No. 5,320,962; Zhou, et al., Proc. Nat'1 Acad. Sci. (USA) 89 :7432 (1992); Jacobson, et al., U.K. Pat. Appl. No. 9304582.1. The sequence of the adenosine A 2 b receptor gene is also known. See, Salvatore, C. Luneau, C. Johnson, R. G. and Jacobson, Genomics (1995), the relevant portion of whichis hereby incorporated in its entirety by reference. The sequences of many of the exemplary target genes are also known.

See, GenBank, NIH. The sequences of those genes whose sequences are not yet available may be obtained by isolating the target segments applying technology known in the art. Once the sequence of the gene, its RNA and/or the protein are known, an anti-sense oligonucleotides lA 1A WO 99/13886 PCT/US98/19419 may be produced according to this invention as described above to reduce the production of the targeted protein in accordance with standard techniques.

In one aspect of this invention, the anti-sense oligonucleotide has a sequence which specifically binds to a portion or segment of an mRNA molecule which encodes a protein associated with a disease or condition associated with impeded breathing, lung inflammation, airway obstruction, bronchitis, and the like. One effect of this binding is to reduce or even prevent the translation of the corresponding mRNA and, thereby, reduce the available amount of target protein in the subject's lung.

In one preferred embodiment of this invention, the phosphodiester residues of the antisense oligonucleotide are modified or substituted. Chemical analogs of oligonucleotides with modified or substituted phosphodiester residues, to the methylphosphonate, the phosphotriester, the phosphorothioate, the phosphorodithioate, or the phosphoramidate, which increase the in vivo stability of the oligonucleotide are particularly preferred. The naturally occurring phosphodiester linkages of oligonucleotides are susceptible to some degree of degradation by cellular nucleases. Many of the residues proposed herein, on the contrary, are highly resistant to nuclease degradation. See Milligan et al., and Cohen, J. S. supra. In another preferred embodiment of the invention, the oligonucleotides may be protected from degradation by adding a 3'-end cap" by which nuclease-resistant linkages are substituted for phosphodiester linkages at the 3' end of the oligonucleotide. See, Tidd, D. M. and Warenius, Be. J. Cancer 60: 343-350 (1989); Shaw, J.P. et al., Nucleic Acids Res. 19: 747-750 (1991), the relevant section of which are incorporated in their entireties herein by reference.

Phosphoramidates, phosphorothioates, and methylphosphonate linkages all function adequately in this manner for the purposes of this invention. The more extensive the modification of the phosphodiester backbone the more stable the resulting agent, and in many instances the higher their RNA affinity and cellular permeation. See Milligan, et al., supra. Thus, the number of residues which may be modified or substituted will vary depending on the need, target, and route of administration, and may be from 1 to all the residues, to any number in between.

Many different methods for replacing the entire phosphodiester backbone with novel linkages are known. See, Millikan et al, supra. Preferred backbone analogue residues include phosphorothioate, methylphosphonate, phosphotriester, thioformacetal, phosphorodithioate, phosphoramidate, formacetal boranophosphate, 3'-thioformacetal, 5'-thioether, carbonate, N-carbamate, sulfate, sulfonate, sulfamate, sulfonamide, sulfone, sulfite., 2'-0 methyl, sulfoxide, sulfide, hydroxylamine, methylene(methylimino) (MMI), and methyleneoxy(methylimino) (MOMI) residues. Phosphorothioate and methylphosphonatemodified oligonucleotides are particularly preferred due to their availability through automated oligonucleotide synthesis. See, Millikan et al, supra. Where appropriate, the agent of this WO 99/13886 PCT/US98/19419 invention may be administered in the form of their pharmaceutically acceptable salts, or as a mixture of the anti-sense oligonucleotide and its salt. In another embodiment of this invention, a mixture of different anti-sense oligonucleotides or their pharmaceutically acceptable slats is administered.

The agents of this invention have the capacity to attenuate the expression of one target mRNA and/or to enhance or attenuate the activity of one pathway. By means of example, the present method may be practiced by identifying all possible deoxyribonucleotide segments which are low in thymidine or deoxynucleotide segments low in adenosine of about 7 or more mononucleotides, preferably up to about 60 mononucleotides, more preferably about 10 to about 36 mononucleotides, and still more preferably about 12 to about 21 mononucleotides, in a target mRNA or a gene, respectively. This may be attained by searching for mononucleotide segments within a target sequence which are low in, or lack thymidine (RNA), a nucleotide which is complementary to adenosine, or that are low in adenosine (gene), that are 7 or more nucleotides long. In most cases, this search typically results in about 10 to 30 such sequences, I. e. naturally lacking or having less than about 40% adenosine, anti-sense oligonucleotides of varying lengths for a typical target mRNA of average length, i. about 1800 nucleotides long. Those with high content of T or A, respectively, may be fixed by substitution of a universal base for one or more As.

The agent(s) of this invention may be of any suitable length, including but not limited to, about 7 to about 60 nucleotides long, preferably about 12 to about 45, more preferably up to about 30 nucleotides long, and still more preferably up to about 21, although they may be of other lengths as well, depending on the particular target and the mode of delivery. The agent(s) of the invention may be directed to any and all segments of a target RNA. One preferred group of agent(s) includes those directed to an mRNA region containing a junction between an intron and an exon. Where the agent is directed to an intron/exon junction, it may either entirely overlie the junction or it may be sufficiently close to the junction to inhibit the splicing-out of the intervening exon during processing of precursor mRNA to mature mRNA, e.g. with the 3' or 5' terminus of the anti-sense oligonucleotide being positioned within about, for example, within about 2 to 10, preferably about 3 to 5, nucleotide of the intron/exon junction. Also preferred are anti-sense oligonucleotides which overlap the initiation codon, and those near the 5' and 3' teimini of the coding region.

This multi-targeted anti-sense (MTA) oligonucleotide approach is, thus, applicable to a variety of other diseases or conditions, including other inflammatory diseases, such as cystic fibrosis, chronic obstructive pulmonary disease, chronic bronchitis, etc.. Other specific diseases or conditions to which this technology is effectively applied are pulmonary hypertension, and cancers.

S.16 WO 99/13886 PCT/US98/19419 Table 2 below provides a number of targets to which multi-targeted anti-sense (MTA) oligonucleotides are effectively applied. Others may also be targeted.

Table 2: Cancer Targets Transforming Therapy Oncogenes Targets ras thymidylate synthetase src thymidylate synthetase myc dihydrofolate reductase bcl-2 thymidine kinase deoxycytidine kinase ribonucleotide reductase A group of preferred targets for the treatment of cancers are genes associated with different types of cancers, or those generally known to be associated with malignancies, whether they are regulatory or involved in the production of RNA and/or proteins. Examples are transforming oncogenes, including, but not limited to, ras, src, myc, and bcl-2, among others. Other targets are those to which present cancer chemotherapeutic agents are directed to, such as various enzymes, primarily, although not exclusively, thymidylate synthetase, dihydrofolate reductase, thymidine kinase, deoxycytidine kinase, ribonucleotide reductase, and the like.

The present technology is extremely important for the treatment of diseases or conditions such as cancer given that traditional cancer therapies are fraught with the unresolved problem of selectively killing cancer cells while preserving normal living cells from the devastating effects of treatments such as chemotherapy, radiotherapy, and the like. The present technology provides the ability of simultaneously attenuating or enhancing multiple pathways.

This approach provides a significant advantage for the treatment of cancer because it permits the selection of a combination of multiple pathways, including primary, secondary and possibly tertiary targets, which are not generally expressed simultaneously in normal cells. Thus, the present agent may be administered to a subject to cause a selective increase in toxicity within .tumor cells that, for instance, express all three targets while normal cells that may expresses only one or two of the targets will be significantly less affected or even spared.

This invention thus provides ah agent, comprising an anti-sense oligonucleotide to two or more mRNAs selected from the group consisting of RNAs corresponding to target genes, to genomic flanking regions, the initiation origin, intron-exon borders, and the like, or the entire sequence of precursor RNAs, including the coding region of mRNAs, non-coding RNA 17 i WO 99/13886 PCT/US98/1 9419 segments, the 5'-end and the 3'-end, e.g. poly-A segment and oligos targeted to the juxtasection between coding and non-coding regions, and RNAs encoding proteins known to be associated with one or more diseases or conditions or mixtures thereof.

The agents administered in accordance with this invention are preferably designed to be anti-sense to target genes and/or mRNAs related in origin to the species to which it is to be administered. When treating humans, the agents are preferably designed to be anti-sense to a human gene or RNA. The agents of the invention encompass oligonucleotides which are antisense to naturally occurring DNA and/or RNA sequences, fragments thereof of up to a length of one base less than the targeted sequence, preferably at least about 7 nucleotides long, oligos having only over about 0.02%, more preferably over about still more preferably over about and even more preferably over about 4% adenosine nucleotides, and up to about 30%, more preferably up to about 15 still more preferably up to about 10% and even more preferably up to about adenosine nucleotide, or lacking adenosine altogether, and oligos in which one or more of the adenosine nucleotides have been replaced with so-called universal bases, which may pair up with thymidine nucleotides but fail to substantially trigger adenosine receptor activity. Examples of human sequences and fragments, which are not limiting, of anti-sense oligonucleotide of the invention are the following fragments as well as shorter segments of the fragments and of the full gene or mRNA coding sequences, exons and intron-exon junctions encompassing preferably 7, 10, 15, 18 to 21, 24, 27, 30, n-1 nucleotides for each sequence, where n is the sequence's total number of nucleotides. These fragments may be selected from any portion of the longer oligo, for example, from the middle, end, end or starting at any other site of the original sequence. Of particular importance are fragments of low adenosine nucleotide content, that is, those fragments containing less than or about 30%, preferably less than or about 15%, more preferably less than or about 10%, and even more preferably less than or about 5 and most preferably those devoid of adenosine nucleotide, either by choice or by replacement with a universal base in accordance with this invention. The agent of the invention includes as a most preferred group sequences and their fragments where one or more adenosines present in the sequence have been replaced by a universal base as exemplified here. Similarly, also encompassed are all shorter fragments of the B-containing fragments designed by substitution of B(s) for adenosine(s) contained.

in the sequences, fragments thereof or segments thereof, as described above. A limited list of sequences and fragments is provided below.

Some of the examples of anti-sense oligonucleotide sequence fragments target the initiation codon of the respective gene, and in some cases adenosine is substituted with a universal base adenosine analogue denoted as which lacks ability to bind to the adenosine Am and/or A 3 receptors. In fact, such.replacement nucleotide acts as a "spacer". Many of the WO 99/13886 PCT/US98/19419 examples shown below provide one such sequence and many fragments overlapping the initiation codon, preferably wherein the number of nucleotides n is about 7, about 10, about 12, about 15, about 18, about 21 and up to about 28, about 35, about 40, about 50, about In one embodiment, at least one of the mRNAs to which the MTA oligo of the invention is targeted encodes a protein such as transcription factors, stimulating and activating factors, intracellular and extracellular receptors and peptide transmitters in general, interleukins, interleukin receptors, chemokines, chemokine receptors, endogenously produced specific and non-specific enzymes, immunoglobulins, antibody receptors, central nervous system (CNS) and peripheral nervous and non-nervous system receptors, CNS and peripheral nervous and non-nervous system peptide transmitters, adhesion molecules, defensines, growth factors, vasoactive peptides and receptors, and binding proteins, among others; or the mRNA is corresponding to an oncogene and other genes associated with various diseases or conditions.

Examples of target proteins are eotaxin, major basic protein, preproendothelin, eosinophil cationic protein, P-selectin, STAT 4, MIP-la, MCP-2, MCP-3, MCP-4, STAT 6, c-mas, NF-IL-6, cyclophillins, PDG2, cyclosporin A-binding protein, FK5-binding protein, fibronectin, LFA-1 (CDlla/CD18), PECAM-1, C3bi, PSGL-1,CD-34, substance P, p150,95, Mac-1 (CD11b/CD18), VLA-4, CD-18/CDlla, CDllb/CD18, C5a, CCR1, CCR2, CCR4, and LTB-4, among others. Others are, however, suitable, as well.

In another embodiment, at least one of the mRNAs to which the MTA oligo is targeted encodes intracellular and extracellular receptors and peptide transmitters such as sympathomimetic receptors, parasympathetic receptors, GABA receptors, adenosine receptors, bradykinin receptors, insulin receptors, glucagon receptors, prostaglandin receptors, thyroid receptors, androgen receptors, anabolic receptors, estrogen receptors, progesterone receptors, receptors associated with the coagulation cascade, adenohypophyseal receptors, adenohypophyseal peptide transmitters, and histamine receptors (HisR),. among others.

However others are also contemplated.

The encoded sympathomimetic receptors and parasympathomimetic receptors include acetylcholinesterase receptors (AcChaseR) acetylcholine receptors (AcChR), atropine receptors, muscarinic receptors, epinephrine receptors (EpiR), dopamine receptors (DOPAR), and norepinephrine receptors (NEpiR), among others. Further examples of encoded receptors are adenosine A, receptor, adenosine A 2 B receptor, adenosine A 3 receptor, endothelin receptor A, endothellin receptor B, IgE high affinity receptor, muscarinic acetylcholine receptors, substance P receptor, histamine receptor, CCR-1 CC chemokine receptor, CCR-2 CC chemokine receptor, CCR-3 CC chemokine receptor (Eotaxin Receptor), interleukin-1p receptor (IL-1pR), interleukin-1. receptor (IL-1R), interleukin-lp receptor (IL-1PR), interleukin-3, receptor (IL-3R), CCR-4 CC chemokine receptor, cysteinyl leukotriene 19 WO 99/13886 PCT/US98/19419 receptors, prostanoid receptors, GATA-3 transcription factor receptor, interleukin-1 receptor (IL-1R), interleukin-4 receptor (IL4R), interleukin-5 receptor (IL-5R), interleukin-8 receptor (IL-8R), interleukin-9 receptor (IL-9R), interleukin-11 receptor (IL-11R), bradykinin B2 receptor, sympathomimetic receptors, parasympathomimetic receptors, GABA receptors, adenosine receptors, bradykinin receptors, insulin receptors, glucagon receptors, prostaglandin receptors, thyroid receptors, androgen receptors, anabolic receptors, estrogen receptors, progesterone receptors, receptors associated with the coagulation cascade, adenohypophyseal receptors, and histamine receptors (HisR). Others are also contemplated even though not listed herein.

The encoded enzymes for development of the MTA oligos of the invention include synthetases, kinases, oxidases, phosphatases, reductases, polysaccharide, triglyceride, and protein hydrolases, esterases, elastases, and polysaccharide, triglyceride, lipid, and protein synthases, among others. Examples of target enzymes are tryptase, inducible nitric oxide synthase, cyclooxygenase (Cox), MAP kinase, eosinophil peroxidase, P2-adrenergic receptor kinase, leukotriene c-4 synthase, 5-lipooxygenase, phosphodiesterase IV, metalloproteinase, tryptase, CSBP/p38 MAP kinase, neutrophil elastase, phospholipase A2, cyclooxygenase 2 (Cox-2), fucosyl transferase, chymase, protein kinase C, thymidylate synthetase, dihydrofolate reductase, thymidine kinase, deoxycytidine kinase, and ribonucleotide reductase, among others. Any enzyme associated with a disease or condition however, is suitable as a target for this invention.

Suitable encoded factors for application of this invention are, among others, NfKB transcription factor, granulocyte macrophage colony stimulating factor (GM-CSF), AP-1 transcription factor, GATA-3 transcription factor, monocyte activating factor, neutrophil chemotactic factor, granulocyte/macrophage colony-stimulating-factor (G-CSF), NFAT transcription factors, platelet activating factor, tumor necrosis factor a (TNF and basic fibroblast growth factor (BFGF). Additional factors are also within the invention even though not specifically mentioned.

Suitable adhesion molecules for use with this invention include intracellular adhesion molecules 1 (ICAM-1), 2 (ICAM-2) and 3 (ICAM-3), vascular cellular adhesion molecule (VCAM), endothelial leukocyte adhesion molecule-1 (ELAM-1), neutrophil adherence receptor, mad CAM-I, and the like. Other known and unknown factors (at this time) may also be targeted herein.

Among the cytokines, lymphokines and chemokines preferred are interleukin-1 (IL-1), interleukin-lp (IL-1)interleukin-3 interleukin-4 interleukin-5 interleukin- 8 interleukin-9 interleukin-11 (IL-11),CCR-5 CC chemokine, and Rantes.

Others, however, may also be targeted, as they are known to be involved in specific diseases t WO 99/13886 PCT/US98/19419 or conditions to be treated, or for their generic activities, such as inflammation.

Examples of defensins for the practice of this invention are defensin 1, defensin 2, and defensin 3, and of selectins are a4pl selectin, a4p7 selectin, LFA-1 selectin, E-selectin, Pselectin, and L-selectin. Examples of oncogenes, although not an all inclusive list, are ras, src, myc, and bcl-2. Others, however, are also suitable for use with this invention.

The agents administered in accordance with this invention are preferably designed to be anti-sense to target genes and/or mRNAs related in origin to the species to which it is to be administered. When treating humans, the agents are preferably designed to be anti-sense to a human gene or RNA. The agents of the invention encompass oligonucleotides which are antisense to naturally occurring DNA and/or RNA sequences, fragments thereof of up to a length of one base less than the targeted sequence, preferably at least about 7 nucleotides long, oligos having only over about 0.02%, more preferably over about still more preferably over about and even more preferably over about 4% adenosine nucleotides, and up to about 30%, more preferably up to about 15%, still more preferably up to about 10% and even more preferably up to about adenosine nucleotide, or lacking adenosine altogether, and oligos in which one or more of the adenosine nucleotides have been replaced with so-called universal bases, which may pair up with thymidine nucleotides but fail to substantially trigger adenosine receptor activity. Examples of human sequences and fragments, which are not limiting, of anti-sense oligonucleotide of the invention are the following fragments as well as shorter segments of the fragments and of the full gene or mRNA coding sequences, exons and intron-exon junctions encompassing preferably 7, 10, 15, 18 to 21, 24, 27, 30, n-1 nucleotides for each sequence, where n is the sequence's total number of nucleotides. These fragments may be selected from any portion of the longer oligo, for example, from the middle, end, end or starting at any other site of the original sequence. Of particular importance are fragments of low adenosine nucleotide content, that is, those fragments containing less than or about 30%, preferably less than or about 15%, more preferably less than or about 10%, and even more preferably less than or about and most preferably those devoid of adenosine nucleotide, either by choice or by replacement with a universal base in accordance with this invention. The agent of the invention includes as a most preferred group sequences and their fragments where one or more adenosines present in the sequence have been replaced by a universal base as exemplified here. Similarly, also encompassed are all shorter fragments of the B-containing fragments designed by substitution of B(s) for adenosine(s) contained in the sequences, fragments thereof or segments thereof, as described above. A limited list of sequences and fragments is provided below.

Some of the examples of anti-sense oligonucleotide sequence fragments target the initiation codon of the respective gene, and in some cases adenosine is substituted with a WO 99/13886 PCTIUS98/1 941.9 universal base adenosine analogue denoted as which lacks ability to bind to the adenosine A, and/or A 3 receptors. In fact, such replacement nucleotide acts as a "spacer". Many of the examples shown below provide one such sequence and many fragments overlapping the initiation codon, preferably wherein the number of nucleotides n is about 7, about 10, about 12, about 15, about 18, about 21 and up to about 28, about 35, about 40, about 50, about Human Receptor-related Antisense Polynuicleotide AAAGCTGAGA TGGAGGGCGC CATGOCGOC ACACOCTGOG C TGC'FITrCT 'ITCTGCC TCTOTOOTCT GTITT=CT GGCCCTGCTG OOGCGCTCTC CGCCGCCCGC CTGGCTCCCO OBGCCCBTGB TGGOCBTGCC GTGOTCTT CCCTCC'ITTO GCTGCCGTGC CCGCTCCCCG GCCTCCTGGC CGGTGGCCGT TOOOCCCGTG 'I7CCCCTOGGG GCCTGGGGCT CCCrCTCTC GCCCT~C'T CTGGGCCTCT GCTGCTGCTG GTGCTGTGGC CCCCCTACA CCGAGGACC CATGATGGGC ATGCCACAGA CGACAGGCGT BCBCCOBGOB3 GCCCBTGBTG GGCBTOCCBC BGBCGBCBCG C GOC GCC GTG CCG CGT CIT7 GOT GOC CGC OG G IT CGC 0CC CGC OCO COG CCC CTC CGC TCC GIT CGC GCC CGC GCG 000 CCC CTC COG TCC COG GTC GO GCC CCC CGC GGC C CCC TCO 000 CTG GOG CGC TGG TOG CCG GG CCG CGC CTC CGC CTG CCO CTT CTO GCT GOG CCC COG OCG CCC CCT CCC CTC noG CTC 000 TCC CCG TG ACA OCO CGT CCT GTO TCT CCA OCA OCA TOG CCG GGC CAG CTG GOC CCC BCB GCO COT CCT CTG TCT CCB GCB GCB TGG CCG GOC CBG CTG GGC CCC ACA GAG CAG TOC TGT TGT TGG OCA TCT TGC CIT CCC AGG G BCB GBG CB TGC TGT TGT TGG OCB TCT TGC CiT CCC BGG GCC CirT TC TGG TGG GGT GOT OCT OnT GT GGG =r TCT TCT on7 CCC BCB GBG CBG TGC TOT TOT TGO GCB TCT TGC CiT CCC BOO 0CC CiT 'I7C TOO TGG GOT OCT OCT iTF GTn ooo C 'FIT CTT CTG TTC CC T IT CCC CTO GOT C17 CC CTC CTG CTC 'FIT 'FIT C ATT TOC TCT CCT ATT ACT TTC TOT OTC CAT 'FIT TTC AiT AAC COA OCT OT enT TOC TCT CCT BT BC'r TTC TOT GTC CBT iT 'I7C Ben BB3C CCB OCT CT 0CC TOT GTC TOT CCT CCT OCT TCG WC CTC TCO TTC CTO CTT GOT 0CC CiT 0CC C OTC CTO CTC CTC COG OCT GTO C OTC OTO 0CC CTO OCT CCC OCT GGT GO CTC CCC TOO CCT TCO CTO OCT 0CC GOC OTO C 000 TCT TOC TCT CCC CCT GOC TOT GOC COT GOT TOO COO TCT TC OCT CCC TCC onT TOO OTO GC TCT CTG AAT ATT GAC CTT CCT CCA TOO COO TCC TOC ITOG OAT TCT CCC GA TCT CTO BBT Ben CBC CiT CCT CCB TOO COO TCC TOC noG GBT TCT CCC GB 0CC T7IT CCT COT TCT CiT OTT onr Mr 000 onT TOO CT- ACA OTA GAO TAO COO A7T CCA TOO CAC GAO CCA TCT TCT TCA TOO ACT CC n-C AAC GAO ACC iTA GOT TTC TOA COG ACT OCT AAC ACO CCA TCT OGA GC BCB 0TB OBO TBO 000 BTT CCB TOO CB0 CR0 CCB TCT TCT TCB TOG BCT CC 'FEC BBO CBC BCC 'ITB GOT iTC TOB, COO BCT OCT BBC BCO CCB TCT 0GB GC onT on TFIT ooo onT TGG Cnr 0CC TFIT CCT OCT TCT Cn BCB OTB ORG TBO COO BiT CCB TOO CBO OBO CCB TCT TCT TCB TOO BCT CC nTC BBO OBO BCC TTB GOT nTc TOB COO BCT OCT BBC BCG CCB TCT COB GC 0CC TOT OTC TOT CCT CCT OCT TCO TTC CTC TCO TTC Cro CTT COT CC CTF 0CC G CTC CTC CTC CTC COO OCT OTO G OTC CTC 0CC CTO OCT CCC OCT COT 000 CTC CCC TOO CCT TCG CTO OCT OGC CCC OTO C CCC BOB BCC BOB CCC GOB CCO BCB GOC COT GOT TOO 000 TCT TC OCT CCC TCC Oil' TOO OTO CC OAT CTC TOA ATA TTOA CCT TCC ATO OCO CTC CTO CnT OOA OBT CTC TOB BTB noe CCT TCC BTO OCO OTC CTO CiT COB TCT COO OTO TCC TOO CCT TCO TOG nTC CTC 71C CTT COT noG CCC TCC OCO 000 CC CCC 000 CCT GGC TOC OCT CCT 0CC CCO CCT CT TCC COG OCT CIT 0CC CTO 000 OGT OCT CC COT OTG 'Ml C CCC TC CTC CTC CTC OCO CiT OTC on- noG COO CCO OCT noG CCC CCC TCC COO COC CTO 0CC COO CC 'ITC CTO CCC TOC OTO CGC onT CTC 17C '7C 'ITC CTG CCT CTO GOC TOT CCT GOC CTT COT COT TCC TCT TCC nTc on TOC COT CCO CGO 000 CCC CCC GOC CT 0CC TOC OCT CCT 0CC CCO CCT CT1 TCC COO GCT cnT GCO CTC 000 COT OCT CCC OTO TOT noG CCC CCT CCT CCT COT CGC OCT TOT COT Mi OG COC CG CTT TOC CCO CCT CCC GOC CCC TOO CCC GGC CTT CCT ooo CTC COT CC COT TCT on7 CTT CiT CCT OOC OCA OCA GAC AOG OCA 000 COA TCA OOA GCA OCO TCA 0CC AAA OGA OGA CCA TCC OGA ACO CAG CTC CGG AAC OCA OCA CAG AGO TOC C GC Boo BOB CBG OOC BOO OCO BTC BOO BOC BOC OTO BOC CBB BOO BOG BCC BTC 000 BBC OCB OCT CCO ORB CGC BOO BCB OBO OTO CC TCT 0CC CTG TCC 0CC COC TCT TCO OTO OCT CG CCC COC TCC noG TCT TOC COC ooo noG on CCT 000 CCT OOT TCT TOC 000 COT 'TC GOT CTC CTO OCT OOT CTO OOC CCC COO TGC OOC 000 TOO CnT OCT onT CTO CCT 000 CTC TCC CCT CTC CTC CTT 'ITC TCC CiT CCT CTC TCT TOC CTC CiT CCT CTO OGT CCT CiT OOC CTC CCC OCT CiT CCC CTC COG COG CTO CCC OCO CTC GTO CTC CCT GOT CCC CTC CCT COG OGT OCT CCT TCC Cnr TCC CCG CTC OTO 000 'FIT OCO 000 CTO OOC TOC CCT 000 000 TCT 000 CCT 'F GO OTC GCC TOO CTO CTO CiT COO 0CC 0C:C TGO OCT TCC Cr0 TGC CCC 'MI CCT Cr0 CTG OOT CCC CCT CCC onT CCA AOC TGC ACC OCA CAC ACC 0CC OCT ACA OGA CAC AOC CAO OCA ACC ACC CAT 000 CAT CCA COC CCA OCT onr CCB; BOC TGC BCC GCB CR0 BCC 0CC OCT BCB COB CR0 BOC CBO GCB BOC BCC CBT COO GBT CCB GGC CCB OCT 0 CTCAOTCOCC CQCAAAGGA TGAOTAATAC ATOCOCCACO ATOATCATAT CCnTrTACT ATGAOGCCOT CTCTOTCCTO *1.22 WO 99/13886 WO 9913886PCTIUS98/1 9419 TCTTTCCTTT GCTCTTGGTG TGTCTGCT GTGCCCTGCC TCTCTGCCCG TGTCTGTCGT GTCT-TTCCT-r TGCTCflGGT GTGTCTTTGC TGTGCCCTGC CTC!TCTGCC CGTGTCTGTC GTGTCTTTCC 1TGCTCTTG GTGTGTCTTr GCTGTGCCCT GCCTCTCTGC -GGGGGTGGCT TCCTGCCGCG TCTCTGGGCC GTCCCGTCCC TCOGCCCCOC GCCGCGCTCG GCTCCTCTCC CTCTGGCCCG GCTCGGGGCG GGGCGGGGCG GTGGGCGGGC GGCGCTGCCC TGCGCGCGGC GCTGGCCCCT GCTGGCC!GTC GGCTGCGCGC TGCTGGCTGC CCTGCTGGCC GCGCCGGGGC CTGTCC!GCCT CTGCGGGCGC TGTCTCCTGG CT-rGTCT-rCC GGCTCTTCTG CTOGGGTGGG GCTGGGCGGC CGGCCC!GGTG CTGGGCTCC TCGOGGGGGG GGGCTCrrCC GGGCTGTCTC CCTCCGGGGC GGGGGTTTCT GGCCGTGGGG GTCTTGCCTG GCCTC!CGGGC TCCTGCTTGT CTTGCCrrCc TTCTCTGGTC GGiTTTGCT CGGGGCTC!CG TGGGTCCCTG GCGCCCOTTT GTGTrTGTC 1TITCCCCTG GCGTCCCTGT GCCCCTC!TCC TCTCCTTCCT CTGCTTCTCG CTCTCCTTTG TGGOGCCCTC CCTGCTGCTC TTGG'TrTGG GCTITI1C TCTTCCTCCT T1TCGTGCG.TGGGCCTCC GCACOCCTCT TGCCACCTCC TOCGCAGGGC AGCGCCTTOO GGCCAGCOCC GCTCCCGGCG, COGCCAGCAG GGCAGCCAGC AGCGCGCAGC CGACGGCCAG CATGCTTCCT CCTCGGCTAC CACTCCATGG TCCCGCAGAG OCOGACAGOC GCBCGCCTC TTGCCBCCTC CTGCGCBGGG CBGCGCCTTG GGGCCI3GCGC CGCTCCCGC GCGOCCBOCB GGGCBGCCBG CBGCGCGCBG CCGBCGGCCB GCBTGC77CC TCCTCGGCTB CCBC!TCCBTG GTCCC!GCBGB GGCGGBCBGG C GCTGCC!CGGC GGGGTGTGCG CTTGGCGCTC CCOTGCTCGG 17CTCTGTCT CCCOGTCCC!C C'ITGCCTGOC GTCTCOGGCC Fr7CGTCCTCT TCCTC'TCTr ccTI'cCGCTC CGTGGGGGCT GCT-rGGTGGG GOCCTGTGCCT CGGTCCCG GGGCTrCTOG CCCTTGCCGT TCATGGTGGC TAGGTGOGGC G1TCBTGGTG GCTBGGTGGG GC GGG GTG GGT BOG CCG TGT CTG GGGGTT1 GGC CBT 011' GGT TGC CTCT TOG TGG TGC GCC GGG CGCG TCT TOG CTT TCT TCT CCT TCG GOC CCT CGG GCC GGT GCT TOT GGGCT CCT CCC GOG COG CCT CCC CGG GCG GOG GCT TCT TGGCG CTG GCG 000 GGG CCT CCTOCT CTG TGG CTG GGC o'rr CCT TOG TOT TCT GO TGGTGG COG GCG TOO TGG CCT CTG TGGGGG CCC GCG OCT GCB GGG GT-rG CCT GTC TGC TrC GTCCTT TOC OCT CCC GGG CCG CCGGG GTG GOT AGO CCG TGT CTG GGGGTr GGC CAT Gil' GGT TGC CGGG CCC GCG GCT GCA GGG 0 ACAGGGOCTG TAATCrrCATC TGCAGGTOGC ATOCCAGTGA AATITAGATC ATCAAAATCC CACATCTGTG GATCTGTAAT AT77ACATG TCCTCTTFCAG ITrCAGCAAT GGTGATC!T AACTGAAGCA CCGGCCAGGB CBGGGGCTGT BBTCTTCBTC TGCBGGTGGC BTGCCBGTGB BBT1TBOBTC BTCBBBBTCC CBCBTCTGTG GBTCTGTBBT BTTTGBCBTG TCCTCTI'CBG 1TTCBGCBB TGG'IMGBTC TBBCTGBBGC BCCOGCCBGO TGOCTCGOTG CTTCTGCCCC TGTTGT-rGCG GCGCTCGGrr OOTGTGOCCC CTGTOGTGCT TCG1TCCCC CTCrTCTCT T-rGTTCGGOG GTTCTTGTGG CGOGCTOCTT GTCTCGTrCC OCCCTGTCGO GCGGOAAGCC TCTCTCCTCT CCCCAOATC COCGACAGOC COCAGGCAAG AACCAGCGCA ACCAGGOCOC OTCCOCACAO ACITFGGAGGC GGCTGCATOC TOCTAC!CTGC TCCAOAAGCG TCCOOTGOCC GCCOCGCC CTOTCGGGCG OOBBGCCTCT CTCCTC!TCCC CBOBTCCGCO BCBOOCCOGCB OGCBBOBBCC BGCOCBBCCB GOGCOCGTCC GCBCBGBCTT GOBOOCOOCT GCBTGCTGCT BCCTGCTCGOOCG GOBBGCCTCCG OTOOCCOCCO COCGTCCGGT GOCCOGCCOCO CCTCTCTCCT CTCCCCGTGO CCCTGTCGGO CGGGTCCTGC COTCCTOTCT CCTM~CMr TGCTGTCTTG TCTTCCCGTC TCTOCTTr OTCTOTCCTC CCCOTCTCCT CCCACTGCT T CTCCCOOGG CTTCCCCGGC 77CGGGTGGC CGGTOTCCCO GGCTCCOGGCO COGCOOCGGC ITCGGCTGCG GGTGOTOOC OCGGGCTGCC OGGTCCGCOC GGCGCCTOGG CCCTTGTGCT GCTTMTGCT TG1TCCG'ITC TGGCTGCTCC GGTCTGTGTr GTGGTTG1TT TGTTTCTTCT TGOTOTOOG CCTTGCGG'IT rrGGCTGTGG GCCC=~GGG GCCTTGGCTT CTGOCTCOTC TGTCC!TCCCC OTCTCCTCCC ACTOC'ITCT CCCOOOGGCT TCCCCOOC'IT CGOTOOCCO GTOTCCCGOG CTCCOOCGCO GCGOCGOCTT COOCTOCOOG TGOTOOCOC GCTGCCGG GTCCOCGCGO CGCCTGGGCC CT-rGTGCTGC 'ITTGCTTG TTCCGTTCTG GCTGCTCCGO TCTGTG17GT OOGrrTrOG TTTC1'CTTG GGTOTGGGCC 'TOGCGG ITrIr GOCTOTGOC CCTIGGGOC CTTGGCTTCT GGCTCCAT CCACATGA'IT GCTTAGA'IM OTGCTOTATC TCTCAGGATr ATCACTGA'IT ACACATCCAA CCAOTOCCAO CCAAAAGOAT OCC!CTGAGGC AAAGGGTrTC CATCTTGAGG CAAATITGAO OACBTCCBC BTOBTCiT BOBTITGTGC TGTBTCTCTC BGGBrTCB CTGBT-rBCBC BTCCBBCCBO TGC!CBGCCBB BBOGBTGCCC TOBOGCBBBO GGTrrCCBTC TTGBGGCBBB =TGBGGBGGGCTB3BGBT OBTCCBCBTC BCTBCCBCOT TGCCCBCCBC BGBGGTCBCC BCBBTOBCCO TGTBGGCBOC TGCCCBBBGG BCBBTrTGCC! BGGCTGG'ITG CBCGBBCTOB TrOGG'rrCCG BOOTGiTMOT GGOBBTGTIT GGOBOBOOT CTGBOTCCBC CGGGBGGBCO TrBTCCBTTT CGBBGCTBGG CGOTBBBGCC! CTBCTBTCTG TBCBCBBCCC CCCTCTGCBG CBOBGTCCTG TCGTGOCGCC TGOGGCTCBG OOTCCGOGC TAAOATOATC CACATCACTA CCACGTTGCC CACCACAGAG GTCACCACAA TGACCGTOTA GGCAGCTGCC CAAAGGACAA MGrCCAGGC TGGTTGCACG AACTGA'TTOG GTTCCGAGfiT GTTAOTGGAG ATOTroGOG AGAGOGTCTrGA GTCCACCGOG AGGACG1TAT CCATTTCGAA OCTAGOCGOT AAAOCCCTAC TATCTGTACA CAACCCCCCT CTGCAGCAOA GTCCTGTCGT OOCOCCTGGG GCTCAGOOTC CGTCCTGTCO TGGCOCCTGO GGCTCTTCTT TTGTGGGCTC ITrOOGTGGCT OTOOCTGTOG TCTCTGTOGT TGCTGCCCTG GOTCTOGOGG TOTOOCCITO OOGCCGTCCT CTOGCTCCTC CTCGTGGGCC CCC GGTGBCB'ITG BOCBTOTCGG CGCGGTCC!CG 'TBBGBGTGG GCC!CGCCAGC CCAGCCACTC CACITOGGOGG CGOTGGCCA OCACOAACAO CACCCAGAOG AAOGGGGGCG GCCCAGAAGG GCAGCCCGCA GGCCAGGATC AGGTCTGCTG COOCCGGAGA TAATGGCATT CACCACOCOG COOCCCAGCG CACOCC!GCOC ATCCOGCCCG OOTCTOACC TGCAGCCCCC GTCTCCTTGG CATrCCTOOG CCCCAOTCAC TCCTCTCCCT GCCCCCCUOG CTOOOGCAOG GACOGGOTO 'BCBTTrGBGCB TGTCGGCGCG GTCCCGTBB GBGTGGGCCC GCCAGCCCAO CCACTCCACT TGGOGCGO TGGCCAGCAC GAACAGCACC CAGAGOAAOG 0000CGGCCC AGAAGGGCAG 23 WO 99/13886 PCTIUS98/I 9419 CCC(3CAGGCC AGG(ATCAGG(T CTGCT(3CGGC CGGAGATAAT G(3CATTCACC AC(3CGGCGGC CCAGCGCACG CCGC(3CATCC GGCCC(GGrr CTGACCTGCA (3CCCCCGTCT CCTfGGCATrF CCTG(3GCCCC AGTCACTCCT CTCCCTGCCC CCCTTGCTGG G(3CAG(3GACG GCCGTGITGT CBGT(3GTGCT (3CCCGMTGB GGTBTG(3CGC TCCBCCIB1T CCCTIT1CTC CTrGTMTCC G1T1'CTCTTG CCGTCTGTG(3 Tlh3' (SEQ. MI NO:2409) Humain Enzyme-related Antisense Polynucleotide (3CT CCT G(3G G(3C CTC CTG GTC CCT CT(3 (CT (311' CCC (3GC CCT (3GB CTG GGG CBG (30( CC(3 CGT BGG( C(3C (3GC TCG CCB (3GB COG G3CB (3CG CCB G3CB G3CB GCB (3GC TCB G3CB TCC T(3G CCB C(3G BBT TCC GGT (3TG CGG( GGC CTG GTG CC CCT GGG CCT CGG( GT(3 CT(3 CCT GT (3CG CT(3 CCT TCT TCT CCT GO GTC CTC (3CC (30(3(CC Cii' GCT (3CC CTG (3CT OT (3CC CT(3 GOG GTC T(3G Gil' CGG( CTG T CCC CB(3 CBG GBC CB(3 TCC! CBT CCB CB(3 C(3T GT(3 BTG BGT B(3C CBT TCT CCT GCB GCC GB(3 (G(CGC GG C(B GCB TCG C MGG(cTr 7C TCC M GGT T T(3B GCG CCB GGB CC3 C(3C BCB GCB G3CB GG(3 COC CGB G3CB TCG CBG C(3( CGG G3CB GGG GGGCTCCCGC C(3C(BGBG(3T

TBT(GGGCTCC

CBGGBCCBCC CGCBCCGC(3C G(3BC(3TITBC BT1'C(CCBCG CBGTGC(3C(G CCGBCBTGBC (3BBGiTrG(GC (3CBBTCBGGG T(3GC(3CCGCB (3BBGT(3GCCT CCGC(3CB(3CT GCBGGGBCBC CBTGBBGG(3C CBC(3C(3T(GG (3CC(CGCTCG CCGGCCcCCCC BCBBTCTCC(3 BG(3CCB(3C(C (3GTGCCCCCC B(3CB(3CBB(3( CC(3(CB(3(BC BCBG(3C3B(3 B(3BCBC(3C(B (3TCGcGCGG(CC (3B(3(3TCBT(3 GTGGG(3(CT(3G (3GCTCC3((3( TCTCT(3CCCC TCC(3T(CTG(3 TGO(3(CTGG(3 (3CTCCGG((3( TCTCT(3CCCC TCC(3T(CC(3C GTG(GGCC(C (3CTC(3CC(3GC CCCCCCCT(3C C(3(3(T(GCT CCC(3CC3C(C (3CC(3(CCT(3C C(3OCCCCTC(3 T(3(3(TCCT(3C T(3(CCG(3(TC C(3(3(TCCC(3( (3(3(T(GGGC(3 C(3B(TC(3(CG (3CC(3B(GGTC CCCTCCBCBT CT(3CTCT(3BC CTGCT(3GBCT CTGG(BTCTGB B(3BTBC(3CCB TG3TB3GGGCG (3(BGT(3((3(C CT(3CTCTCCC GG(CCTCC(3BT (3BTCTCCCCT GCCTCB(3CCC CB(3T(3(3TB(3 GBGBBB(3OCC B(3CBOBB(3CB GG(B(3T(3(CT(3 CBTC1TTCCT (3(T(3((3(CCT (3CTCTCCC(GG CCTCC3T3T 1GCTGGGTG TI1CCC(3TC TCTGGTCT(3C CiTC3((3((3' C(3T CCGG((3(CT(3C BGCBBCCTCB TCB(3CTCiTrG CCT3(B(3T(G CTCB(3CCTGGc (3CCT(3CB(3(3( CCBCCB3(B(3 BBT(3GCBGCB BGG(BT3(C(3B (3GGTCCTCBT (3(CT3C(3(TC BCB(3BTCCTC TBGCTB(3(CB (3(GT(3BCCBG B(3BGG(GC (3(3(TCC TCB TG(3 CT(3 (3(33(CC TGG (3CC T(3C B(3( (3CC GCT Mi (3CC T(3G B(3T (3(C TC (3CC CB(3 BGT Cii' CCC T(3( T C(3CT(3CBBTC T(3CTCCGG3( CTGCBOCBBC CTCBTCB(3CTC T1'(3CCT3(B3T( (3CTCB(3CCT3( (3CCT(3CB(3(3( CCBCCB(3(B(3B BT(3(CBGCBBG (3BT(3GC(3B(3(3 TCCTCBT3(C T(3O(3(TCBCCT O(3Bo(3BGGGB (3BGCB(GG(3(3 TCCTCBT(3GC TGG((3(TCCCT CTCTCCCGTC CT C(3( Mii CCT 1T(3 CG TC 7rG (3CC C(3( (3Cr CC(3 (3GT G3 CCC (3CC C(3C CC(3 CC(3 (CC (3CC G3C CCC (3CC GGG CTG( TCC CC(3 CCC C(3C CCC (3(C CC(3 (3(3(CGC (3(3(3 (3C(3( CCC TCC C(3C CCC TCT (3G (3CC (3(C (3CG (3(C (3TC (3(3CC(3 crc (3C( CCT (311 CCC Tcr ccr CCC CCT 3T(3 C (3CC T(3C crc Tr(3 crc i'crGCc (TC C(3C TC C cr CTC CC crc TCC TC3 (3CC (311 (3CC T(3T G3C T(3T CC(3 TCC TGT C(3C CCT TCC (3T( (3T( C TGT TGT crc ii'C T(3C CCT C O(3T (3T( crc (3T( CT(3 (3T( (3T( (3T( ccT CT(3 CCC (3T( CTC csCCCr( ccr C3(3C CT(3 (3CC TCr TC(3 (3GT (3T(3 (3CT TG (3(3(CTC TCT T(3( TTG( CCC TT-r CT-r CTC GT(3 (3TG ccr CTC CTC CCT (3(C 1i'( (3TC (3T T(3T CTG GGG (T3( T(3C TCC TCT CCC Mli CCC T(3C T(3( CC(3 MF GT CCT Gil' iiC T(3T Cii' CCT Cr 17C crc CT(3 MT CTC C(3T TrG (3Cr T(C T(3C TT(G C(3( (3(C T(3T CTC C Cr' (3CC CCT GT(3 (3(C Ti'7 CCC T(3( TCC G(3T Cii' crc CiT (GT C (3CC CT1' CTT (3(T CTGGCT CGT Cr(3 TCT 77IT TCC T1'C C T(3(3G (33TGG( CC(3 'T(3 T(3( (3C( (3T( TGG( TCC (3CC T T(3C crc T(3C T(3( TCT ii'C -CTC(3GTBGBC GC(3CTC(3BBC TCGG(GT(3(3(C CGG(T(3(T(3B( CO(3C(GC(3BCB C(3CO(BB(3(C CCTGC3C(CC (3ROBTCBCcr(3 CBGGG1(BBG( TBG(3CiT(CB GCB(3GBCTCC CB(3(BGGO(T3 BCB(3CB(3CCB (3TB3BGCTcBC CTC(3TCCTTC BTG(3TBCC(3T CO(3T(3T(GT(3 (CBC(3(3(CT3 T(3T(T3BB(3( C(3B(CT(3(3(C CCC(3TrTGCT GCTCC!TC(3T( CC(3CCTC3TC C'TrCA T(3G TA CC(3TCGG(TGT (3GT(3(CCTC(3 (3GT(3(3CC(3( T(3(TGGG(3(C(3 C(3C3C(3CTC( C(3TGGCTCC3 (3CTC'rrCTrr CCCGGCTCCGT CGG(CCC(3((3( (3CCiTG(3TCT CCcC(3GTCCr TCBT(3OTBCC (3 BCC(3(CG(3B( CC(3CCB(3(3(T G(3BCT3(3(B( TGG(3 TCTC CCC(3CCcrrrC TCBCCCBCC(3 C(3CT(3B(CTC B(3CGCCTBBG BCT(3CT(3i7 CTO(3B(CTCC 'F1'(3(CBBGCC BCBBBCB(3CB GB(3B(BBBBT CBT(3B(CBBB TBBTCCB'rJC T(3BBBBBBB(3 (GBTCBBBBB CCTCCC(3TFC CCCGiTC3CC T(3(C(3C(3C(C T(3C(3(3crCC TC(3T(G'rrr CTCCCC(3CCG ii'CTCC3GTC T(3'1T(CCiM (3TcIGCTTC'I T(3TCIrrr( (CTG1TC'T17 TCCTGCT1'G( CGTCT11CC ii'TCTT1'('r( CTCGG(TT(3TG GGTCC(3CT3( TCCTI'GCCC T(3T(3T(3iC T(3CTGCCC(3T TC(3CrcGGC( C(3CGCT3CGc3 GTiTCcCT(3T (3GTITCTCCCQ CGCCGiTCTC CG(3TCTcrrrc CCii'TOTGO(3 CT1'C'TGTCT ii"1iG(Gi'G TCiTIi'CCrG CTTG(3CG'TCT T1'TCCT1T7CT 'T(3TCCGG TrG(TG3(TCC (3CTG(TCC'Fr T(3CCC(TTT (3iCT3CT3 (GB(3CT(BTB CTG3CBG3Arr7 CB(3B(G(3BB(3 BBCCCTG3BTB3 CTCBCCB(3CT TCB(3CTCTGG( B(3CBCBB3B( BBBOB(3CB(3C B(3G(B(B(3 OBB(3BB(3CB( CBTCT1'CCCB GBB3(CT(C CTGB(3CBBBT (3CTG(3iT=C CTICCB(3TC iT(3((3'TIT TBBCrCCCB(3 BB(3(CBB(3BG B(3((3(CBBGG( C(31=iCTTC TcC(3GCT3GT iTT7CCiT1CC T(3(CAGT3(3G TGG(3(GT(G(3 (3(T(3OciTG CiTCC'T3fl Ccr(3(33(3(T3 TCCTCT1'(CT CT(GcGCMr CTCCCCTMi~ CCrrCCTGTC T(3TT1CCTG G(3CTCTCCT CTGTCTCrOT GCrrGCCC TG(3CCccrT CcrccTccro TCrCCT(3wC CTGTGrnTC( CCCGTCT'rCC CTCTCCTGAC CTCCTT1'CC TCC(3CTGGGTy GG(3(CCCTOC CTGii'CTCro Crccc'rGGCT TG(3iTi TCGTTGTC ii'CiicrcCTT (3TTGG(CTGGrC iiTCTCCTrC TITMGTCii'C CrG3GT(3CCC C'TCT'CCTT1 Tr1'cGGGTCC ii'GTGCii'G GG(CT(GGG WO 99/13886 WO 9913886PCT/US98/1 94 19 GCGTCITOOO GTGCBGGGCC CBTCCTOCTG CGCCTGGGCG CTGCTGTOCG TCCGTCTGCT GGGCCO GGTGGCTOG CCCTOCITGC CGCACGACCC CGGGCCGACC CGAGGCTCGG GGCTGTGT TCTGGCGCTG GTGGGCITTG GCCCCTCTOG GGGCTGGGTT TCCTGCTOCG CCTOOGCGCT GGCGTCITGG GGTGCGGGGC COGOOGCCG GGGGGCCGCT GITCOTGGGC CTGGGGGTGC CTGTGOCTGC CGGTTGCCCC GGITOGTGGC GCCGTCCTGC TGCCGGTCGT TOOCTGOGTC CCCCCGCCCG T17~CCTGOOGG TCCGCGTGGO OTOCTCCOGT TCCTCGTGCC GCTGCTGCCT TGTCTICCG GCCGTGOCGO CGTGOTGGTC COCCCCCCCT GGCCITCTGC TCGGGGTCTO OCTOITrGCC GGTGCCCTTO GCGGCGGTCT TCITCCTGGT GGCTCTGGGC CCGGCCGGTC TCGCOTCT CGTGITCGCT CI7GTGCTGT TCCGGCCGCT CCTTCCTCIT CCOCCGCCOC CGCTCCCCGC CCGCTCOTCO CCCTGGCCCG GCCTCCTCCT OOCCGCTGTC TCGGGCGGCG GCCITOGCGC TCCOGMGGG GCTGCCTCTG OCOCITCCOO CCCTCGGCCT GOGCOCTCTC ITCCGCCTGT GCTGGTGGCC CTCGTGGGCC CCTCCTGGCC TCCGGTG TCC TOTGOTCCCC CGGCTOOTGG CCGOCCGGT TGCGOCG TGGGCGCCGG CGGGTCCTCC GGGCTOCCCT TCTCCGCCOG GTCCC0CG CTCCTGCTOT TCCCTGOOCT CITCTOCCTC TCTCCTGGGT GGGTGCTOOG TGCCGGTC TCCGGGCTTG CCCCOCGCTG CTOOGCITrC TGCGGTCITT OOITrGTCTG TGGCCCCGCT CGTOTCGCCC TCCGTCOCCC GTCGCCGOCC TCOTCCCCTC CTGGGTGCGC GOCGCTGG TCCTGGCGIT ITrCTCCTrC CTOOGCOTCT TGOOTGCBO GGCCCBTCCT GCTOCOCCTG GOCGCTGCTG TGCGTCCGTC TGCTOGOOG CCGOOTOGC TGGGCCCTGC 77GCCGCACG ACCCCOGOCC GACCCGAGGC TCGGGGOOCT GTGITCTGOC OCTGGTGGGC ITGGGCCCCT CTGGGGOCTG OO'IMCCTGC TGCGCCTGGG CGCTOGCGTC ITOOOGTGCG GCCGOG GCCOGGGGC CGCTGITCGT GGGCCTGOGG GTGCCTGTGO CTOCCGOITO CCCCGOITOO TGOCGCCGTC CTGCTGCCGG TC1TrGGCTG GGTCCCCCCG CCCO1T]CCT OGGGTCCGCG TGGGOTGCTC COITrCCTCO TOCCGCTGCT GCCTGTCIT TCCGOCCOTG GCGGCGTGGT OOTCCGCCCC CCCTGGCCIT CTGCTCOGOO TCTGGCTOGT TGCCGOTGCC CITrGCGGCG GTC'ITCITCC TGGTGGCTCT GOGCCCGGCC GOTCTCOOOC GTCTCGTGT CGCTCITrTG CTGITCOGC CGCTCCITCC TCITCCGCCO CCGCCGCTCC CCGCCCGCTC GTCGCCCTGG CCCGOCCTCC TCCTOGCCGC TGTCTCGGGC GGCGGCCITO GCGCTCCOTT TGGGGCTGCC TCTGGCGCTI' CCGGCCCTCG GCCTGGOCGC TCTCTTCCOC CTOTGCTGGT GGCCCTCOTG OOCCCCTCCT GGCCTCCGGT GTCCTGTOOT CCCCCGGCTG OTGOCCOGOC CGIGGCG GGCGTGGOCG CCGOCGGTC CTCCGGOCTO CCCITCTCCO CCOGOGGTCC CGCOCTCCTG CTITrCCCTG GGCTC'TrCTG CCTCTCTCCT GOGTGOGTGC TOGGTGCCGG GGTCTCCGGO CTTOCCCCGC OCTGCTGOGC OITCTGCGGT CITrGGGTTO TCTGTOGCCC CGCTCOTGTC GCCCTCCGTC OCCCGTCGCC GGCCTCGTCC CCTCCTOOGT GCGCGGCGOO CTGGTCCTGO COTITGCTC CTTCCTGG CTOCCCCBGT T1TGBTCCT CBCBTGCCOT GGOGBOGBCB BTGGCTGCCT CCCCOGGTr TCTGCTGCT OCTGCTrCIT TCCCGTCTCC CTTT1CCC GTCTCCITI TGCCTCn7Gr GGITCCTITT GMTCTGGCC TGCITOOTGG CGGCITOTGC O'I=CCTCTC TCTTCTCTTG GGTCTCCOCT TCTCOTCCTG CCT=~CCTG TCTCTGTCOC GCCG'ITCCTC CTCCGOCGTC CTCCTGCCCT OTGCTG'TrrO CCTCGGGTGG TOCOOOTCCC GGTGCTCCCC COOCGGOCCG GCTGOTGCC TGGOCCTOTC TGGTGOOTO TGOOCCOCT GGrrGGG TOTGGTGGOC TCITCTGTGG CCTGTGGGOC TGITGGTGTC TCTGTGGGCG TOTGCTGGGT CITrGGOiT CCTCCC1TrT OCTGGGTOCG OCCTCCCCGC CCCCCITrCTG GOCCGGTGGC CTGGCTCCIT OTGGGCOCIT CTGGCTCTO CCCTGTCCIT CITCGCCTCG TGOCTGCTOG GCTGC-3' (SEQ. ED NO:2410) Human-Factor Related Anti-sense Oligonucleotide 5'-CCT Car TCC TOO Tar OTC TOC CBG BCB BBT ITG GOB BGT GBB CBG TGG BBC CET GIT TCC CBO Tar aro BOC TOT GOC 0CC CTG CTO r CTT CTG cT-TCC CIT GGT GGG ITG C C Gc a GOT TGT TCT GGG GIT C ITO CTG CCC CIT CTG TCC C TOT ITO CTG OTG Tar OCG C CCC CBB CBO BBO BBO CBG BCB BBT ITG GOB BOT OBB CBG lT TG BBC CBT GIT TCC TOT OCG CTC OGC CTG GTC CCG 0000G TCT car CIT G'rr o'rr OC ITG CGC CTC CTO CTG GOG GT CC CTC TGT Tar TGT TIT GOG GOC GGG CCC GGC CGT TGT CIT G GIT TGG COG =r CCO ITG 000 ITC TCC TGG CCC 000 car TGC CC 0CC CGT GGT CCC GOC ITC ITrCCT GTC TCC GTC TCG OCT CIT CTG GGG CCT TGC OCT GTC Mli GOT G 5*-OCB CCG TCC BGT OBT GOT OCO 0TB CIT GTC OCT GCB GCG CTC GOC aro GTC CCG GBO BOC GCO COO GCC 000 GOC TOC TOO G OGT TGO CCC GOG OTO CCC C occ oar GGG TOC car COT CCT CTO COO TC OTO TCT CCT GOC TCT GOT TCC CC OCT OCO CCC GIT OTC acT TGO GOT 0C CaT C OCT CCC 000 Tar GOT TCr TOT OT TOO 000 TCC CIT Mli 000 CCT GiT OT 0CC OTO OCT TGT OTO ITrCGT ITC.TGC CCT GTC CTC COG COT CCC COG BOC CTC CCC 000 GCB GOB TOB CIT ITO BOO 000 BC .B CBO BTO Tar OG CBT TOC CBG GTC CTO 0GB BCB OBO CCC COB GCB 0GB CCB GOB OTO COO GCB OCO COO OCC 000 GOC TOC TOO OBO CCB TBG COB OOC TOB 0 CCT CIT ITC TOT 'liT TCC C CTC TOC CIT TOT ITO GOT TCO CIT CCT ITC TO.C ITC ITC C CTG TOT CTC CTO TCT CCG CIT 'liT Tar TC OTC lTr GIT GIT ITC Tar TCC ITO CTO BGC BBO BTB TCT BOB ITC TOG GOT OOT CTC OBT 'li BBBB oar TOB OBB oar GCB BBC BIT BTC CBB BGT BTB Tr7 OBO OCT CCB BOO BTC BCG BCC BTC ITC CCB GOC BIT 'ITB BGT TGC TOT COT BBO TOB OBO aro BOB GBB Bar OTO BBO CBB TCB TGB CIT CB3B OBO ITC 'liT TCB CCC OIT CIT GGC ITC ITC TOT C CGT TGCTr C GTr TC CC TOT GG CITrCTC =ITGTC CC CCC ITC GGGGGC TGO TOOGGC COTCCT TOCCTO CTO 0 OIT CT GGC ITC ITC TOT CCO T TGO CIT CTC GIT GTC CC TOT 000CI CTC GIT OTC CC CCC ITC 000 WO 99/13886 PCT/US98/1 9419 GOC TGO TOG GGC CGT CCT TGC CT0 CTO G 'T TCT CT!' TCG CiT TCT =r CGT CTC CTG TTC CTC C7717' iTO CTG M~ 'I CTC CT!' CT-r CTC TCC MF! CT!' 'TC '1T TCT CT!' TCG CT!' TCT 'FI COT CTC CTG 'F!C CTC CT!' 7F! iTO CTG 'FT'I CTC CT!' CT!' CTC TCC TF!' CT!' 'F7C CTC TOT CT!' GiT CTG GTC C1!' COT 000 OCT CTO TOT CGC OTO 0 OTO COG CCO TOO CC GOC 0GB CCB 0GB G'F! 0GB GCB GOB GCB GOB COG GCB GOC GOC TCB TOT TI'O OBT COO CBG OBO GCB CTC CTC TOO TTG' OCT TCC 'FEC 0CC GOC BCB TOC TBG CBG OBB GBB3 CBG BOO 000 BBG CBG iTO GOB GOT OBO BCC CBT TBB TBG OTO TCO B TCCCTGiTTTC CCCCCTCO 'F!'CTOCO'FT OCC'FGGCO 'ITFIOFG O1I IICTCTC TCCOTC'IC 'TrCTCCCCT OTOOOBB'FIT CTOTGGGGBT OOCBTBCBCO TBOOCBOCTC CBBOBOCTBO CBBBCTCBBB TOCBOBBGCB TCCTCBTGGc TCTGBBBCOO TGOOAA'IC TOTOGOGBTO OCATACACOT AOGCAGCTCC AAOAGCTAGC AAACTCAAAT OCAOAAGCATC CTCATGOCTC TGAAACO OGGOTGOCT TCCTGCCOCG TCTCTOOGCC GTCCCGTCCC TCOOCC!CCOC OCCOCGCTCG GCTCCTCTCC! CTCTOOCCCO OCTCOGGGCG GOCGGGOCO OTGOCOGOC GOCGCTGCCC TOCOCOCOOC GCTOGCCCCT GCTOGCCOTC GOCTOCOCOC TOCTGOCTOC CCTGCTOGCC GCOCCOOOOC CTGTCCGCCT CTOCGOGCOC TGTCTCCTOO CiTOrTCF!CC OGCTCiTCTO CTGOOOTOGO OCTOGCOC CGOCCCOGTG CTOOOOCTCC TCOOOGOGOO GOOCTCTI'CC GOCTGTCTC CCTCCGGGC GGGFT7CT GOCCOTOGOG OTCUOGCCTG OCCTCCOGoC TCCTGVITOT CiTOCCF!CC iTCTCTOOTC OGiTOGTOCT CGGGOCTCCG TGGOTCCCTO GCGCCCO'FI OTOTJT!'TC iTTTCCCCTO GCOTCCCTGT GCCCCTCTCC TCTCCTTCCT CTOCiTCTCO CTCTCCT-TTG TOOGGCCCTC CCTGCTOCTC TTGGT=TGG GCTITITIC TCTITCCTCCT TMICGTGCO TGGGCCTCC GCACOCCTCT TOCCACCTCC TOCOCAGGOC AGCOCC TOG GOCCAGCOCC OCTCC!CGOCO CGGCCAOCAG OOCAGCCAGC AGCGCGCAGC COACOOCCAG CATOCTI'CCT CCTCOGCTAC CACTCCATGG TCCCGCAOAO OCOGACAGOC GCBCGCCTC T!'GCCBCCTC CTGCOCBOGO CBGCOCC'FrG OOOCCBGCOC COCTCCCGOC OCGOCCBOCB OGGCBOCCBO CBOCOCOCBG CCGBCOOCCB OCBTOC'F!CC TCCTCGOCTB CCBCTCCBTG GTCCCOCBGB OGCGGBCBOG C GGOGTOOBBB GOTITOBOT BTOTC'FITBT GCBCTOBCBT CTBBG'TF!CT TBGCBCTCCT TOOCBBBBCT GCBCCTT!CBC BCBGBOCTOC BGBBBTCBOO BBGOCTGCCB BGBGBOCCBC OGCCBOCiTO GBBOTCBTGT T!'BCBCBCBG TOBOBTOOT!' CCTTCCGGGC iTOTOTGCTC TGCTGTCTCT TOGiTCC'FrC COOTGG'FrC 'FICCTOGCTC iTOTCCiT'C TC'FI'O CCCT TOOC CGOBOTGO OOTCCTOGBC OOCBCTGBBG OCBTCCBGOG CTCCCTT!CCB GTCC~T'! TCCOCTGCCB OCBCCCCTT!C BTT!CCBGBGO CTGBTGOCCT CCBCCBOOOB CBTOB1TBOO TBGBBBTG GBGOCCGOCC TCCBCCBGO BCBTGGTCCT TC1TGTCCGC TOCCTCTCTG GGO'I'ICOG TCTGGGTGGG CTT'TCCTCCT OGGOCTGCTG CTGOCTCT7! CTIMTriT CTOOCCTOOT GCTCTCTCOT OCCC'FITCCC iTOOGTOTCT TO TTITT OCCTCCBCCB GGGBCBTO GTCTIT!' CTGGCTCOT GCCCCBTCCC GGCTTCTCTC TOGiTCC!GTC CTCTGTGOTG 'TGGCCCTO C'FCCTIG CCTO'TrGAGO GOCAOCAOT TOOOCCCCAA AOOCCCTCTC GITCACC!FrC TGGCACOGAG'F! GCATCCCCATA GTCAAACTCTOGTOOTCGTGT CATAGTCCTC TGTGGTG'FF! OOAO'ITCCA TCCCOOCF!C TCTCTGUrc CAAGGGAGB GGGGGCBGCB GiTOGGCCCC BBBGGCCCTC TCG'ITCBCCT TCTGOCBCOG BGTTGCBTCC CCBTBOTCBB BCTCTOTGGT CGTGTCBTBO TCCTCTGTOG TOTITOGBOT TI'CCBTCCCG GC'iTCTCTCT G1TrCCBBOG GB, GOCBCOGGOG CBGTGOCOO GCBBTGTBOO CBBBGCBGCB GOTOTOOTO TCCGBGGBBT BTGGOOBOGC BOBTGCBOGB OCOCBOBGOO CBOTBOCBBT GBGOBTOBCB GCGBOOCOTO CCGCGOBGBC CUTCBTGGTB CCTGTOGBOB GGCTOTCGOB GOOOOTGTGG TOTCCGCTTG GCOOT!'C=r! CGGGTO'T!'C 'F!CTCTGGGT TGGCCTGCTG CTCGTCOTGOT COCTCCGCTC CCGO'F!'CGT CTCOCTCTOT CGCCCCiTCC TT!CC'TOGTCG TOT!'CCTCCC 'FICCiTGCCT CT OBTOMTITT! BCCBBBOCBT CBBGBBTBGC 'ITTCTBTCT BBGGBTCBCB 'FTBGBCBTB OOBBBBCOCT GTBOOTCBGBB BGBTGTOCT!' BCCTI'CBCBC BOBGCTGCBO BBBTCBGGBBGG CTGCCBBGBGBO CCBCOOCCBOC 'TGGBGTCBT G'FIBCBCBC BGTGBOOTOC TCCOGTOGCT 'FTIGCTwrGT GTOCTCTGCT GTCTCTG TTC CTTCC!GGTGO iTTCT!'CCTG GCTC1TGTCC TITCTCTrGO CCC'ITGGCCC C'TOGBOCBOG BBGCTCTOOG OCBGGGBGCT GOCBGGGCCC BGGGOTOG C1TCCTOCBC TGTCCBGBOT GCBCTOTGCC BCBGCBGCBG CTGCBOGGCC BTCBOCTrCB TGGOGCTCTG GGTGGCBOGT CCBOCCBTOO GTCTGOGTOG GOCTOGOCTO CBGGCTCCOO OCGGTCCBOCCBTGOOTCTO GGOCTOOG CTOCBOGCTC CGCGOCO GOTOCGOCT OCOTOCTOOG GGCTOCCCCG CAOGCCCTGC GOTCCBGCCB TGOGTCTGGG GOCTGOCTO CBOOCTCCGG OCGOCGOOT OCOOOCTGCG TGCTOGOOGC TGCCCCOCAG GCCCTGC GCBCCGCCTG GBOCCC!TGGG OCCCCCCTGT CT'C'TrGGOO BGCGCCTCCT CGGCCBOCTC CBCGTCCCOG BTCBTOC'FI CBGTOCTCBT GGTGTCCTI CCBGGGGBGB OBGOOCTOG TCCTCTGCTG TCCTOrCTGG TGCTCBTGOT GTCC'FICCO CCCTOGOGCC CCCCTGTC1 c1TrGOGCCT C'TcCCTCTG GGCCGTCT CTCTCCCTCT C'TGCGTCTC TCTCMICTC TCTCTCTCiT CCCCTICCC GCTCTItCTG .TCTCGGTGTC TGO1TCTrC TCTCCGCTOO CTGCCTOTCT OGCCTOCGCT CiTOOCCTOT GCTG77CCTC CTCCOiTrCC TGTCCTCTCT GTCTGTCGCC CCCTCTGGOO TCTCCCTCTO GGTGOTGGTC iTTO~CiTO GGCTOGGCTC CGTGTCTCCB GTOCTCBTGG TOTCC!GCTGB GGOBOCOTCT OCTOOCOCTO GTCCTCTGCTOTC C'TrGCTGGTG CTCBTGGTGT CCMICCOCC CTGGGCCCC CCTOTC1TTCT TGGGGCCTCT TCCCTCTOOG GOCCOTCTC TCTCCCTCTC* iTOCOTCTCT CTC'FICTCT CTCTCTCiTC CCCITTTCCCO CTC'FT7TGT CTCGGTOTCT GGTFICTCT CTCCOCTGGC TOCCTGTCTG GCCTGCOCTC TTGGOCCTGTG *CTGTTCCTCC TCCGGiTCCT GTCCTCTCTG TCTGTCGCCC CCTCTGGGGT CTCCCTCTOG COTOGTGGTC TrGO'TGCT!'O OOCTGOGCTC COTGTCTCCB GTOCTCBTGG TOTCCGCTOB GGGBGCOTCT GCTOOC CTOCTGBOOC 1TOOGTCTCC GOOCOBTFCT CTGCBGBBGB TGCTCBBBGO GCTCCGGCBO 'FCCTCC'F!G BTCTGOTCOCT GTCGTB3CCBG TCGOBCCBOT 26: BBTTCBGBTC BTCBTI'GGCT CCTBTTTCTT CTGCBBBCBG CTGBGTGGBG BCBBGBBBBB BGBCTGCCBB GGCCBCGBGG BTTCBTGT TGGB1TTTTGC GBCGGBCBOT CCCGCOGGGT GCTGAOTrC TCTGGTTCCT CCGBOCGCBC GTGGTCGCTC CGCGTCTC TOGTTCCTCC GGTCCCGCGG GOTGCTOTCT GGTCGCTGTC GTGGCTI7GGG TCTCCGGOCG GTrTCCTTCC T1TTCCGC COGCCCTTCT CACTGGAGGC ACCGGGCAOT CCTCCATGOO AGGGTTGGGC TfGGCCOGGG CTGCCCOGTG CCTCCTCTTG GCTGGTCCCT CGTTGTCCTT OOGCCCCGC TCCCGCTGCT CGGCCTCCGT GTrCT-TGGC CTCTTGCTCC GCCTOCTGTC UOrTCCCGTC CCCTCCTCGC TrroCGT-rCC CTCTTCCTTO TCTTCCAGGC CTTCCTCCGC TITCCGCTGCT GGGGCCCOCG CCGGGGGGGC GCTCGGCTCC GCGGCTTCCT CCCCGGCTGG GGGGTCCTGG TCTCCGGGGC CTGCGGCTCG CGCTCGOG GCTGCGTGCG CCGCGCGCGG CGTCCGCGGT GGGTGGCGCT GTCCCGCCGT GGTOTGTCTC CGTTCTCGTC CTGCGCCGTC CTGGTCTOCC CGTGGGOTCC TGGGCGTGGT GGGOOCOTC TGOTGCCTCG TCTGCCCCOT GGGGCTTCGG GCTCGGOGCT GT-rCGTCCCC CCTGCCGCTC TGTGGCCTCC GGGGCTCCTC GTITTCGCTG CTTCGGGTGT CCTI7CTCGGC GTGTGGCCCC GGGTCCCGGC CCTGCTGOGC TGGGCGGGT CGCTGCCCTG GGCTJTCTGGC CCGTCTOGT-r GTCTGTCGGT GCTTOTCTCO GGU17CTGGC CTCTGTGCTG GGCGCTfrCTC TGCCTCCTGC TCCGCCCTCC TGGTGGCTCG GCTGGGGGTG CCCGTOCGGG GGTGGGTGTG GGGTGTTC GGGGTCCTCC CCrrCCC orr TCA TCT TGG CIT TAT CCTCT CCC C17 GTT~ CCT CCC CTCT CCT GCT CTG ORG TCT CCT C TfC CCT CCC TCC CCT 0CC GTG TTG TCT GTG GOT GTC OTT TCG CTC TTG ITO CCC TGG GCC CIT CCC TGC TGG GGG GGA GYIT TCA TCT TGG GTT TCB TCT TGG CTT TBT CCTCT CCC CIT OlT CCT CCC CTCT CCT GCT CTG GRG TCT CCT C 'rrC CCT CCC TCC CCT GCC GTG ITO0 TCT GTG GGT GTC GIT TCG CTC UTG UTG CCC TGG GCC CIT CCC TGC TOG GGG GGB GTT TCB TCT TGO OGG GOB GTT TCB TCT TOO CIT T CCGTGITGTC BOTGOTGCTG CCCGTGBG GTBTGGCGCT CCBCCBBT-rC CCT'TTTCTCC TTGT1TMCCG 'rrrCTC-rrOC CGTCTGTGGT T-Y'(SEQ. ID NO:2411).

Human Adenosine A, Receptor Anti-sense Oligonucleotide Fragments GGA GGG CGG CAT GGC GGG-3' (FRAG. NO: 1657) (SEQ ID NO:1) CGG GTC GCC 00-3' (FRAG. NO: 1658) (SEQ ID NO:2413) 000 CBC BGG C-3' (FRAG. NO: 1659) (SEQ ID NO:2414) 5'-GGC GGG CBC-3' (FRAG. NO: 1660) (SEQ ID NO:2415) GGC CTO G-3- (FRAG. NO: 1661) (SEQ ID NO:2416) GGO CGG C-3' (FRAG. NO: 1662) (SEQ ID NO:24 17) GOB GO-3' (FRAG. NO: 1663) (SEQ ID NO:24 18) 5'-00 CTG GGC-3' (FRAG. NO: 1664) (SEQ ID NO:2419) 5'-GC GOC CTG GAA AGC TOA GAT GOA GGG CGG CAT GGC GGG CAC AGG CTG GGC-3 (FRAG.1) (SEQ. ID NO: 11) GGC CTG GAA AGC TGA GAT GGA GGG CGG CAT GGC! GGG CAC AGO CTG GGC-3' (FRAG 2) (SEQ. ID NO: 12) CTG GAA AGC TOA GAT OGA GOG CGO CAT GOC GGO CAC AGG CTO GGC-3- (FRAG 3) (SEQ. ID NO: 13) A G G A G G G A G G CCAGCGGC3 FA O 4 5'-C CTG GAA AC TGA GAT GA GGG CGG CAT GGC GGG CAC AGO CTG GGC-3(FRAG (SEQ. ID NO: 1) 5'-CCTG AA AGC TGA GAT GA GGG CG CAT GC GGG CAC AGG CTG GGC-3' (FRAG (SEQ. ID NO: 1) 5'-TG AA AC TA AT GA 000 CG CAT GC 000 CAC AGO CTO GGC-3 (FRAG (SEQ. ID NO: 1) AA AC TOA AT GA 000 COO CAT GC 000 CAC AGO CTO OOC-3 (FRAG (SEQ. ID NO: 1) AA AC TA AT GA 000 COO CAT GC 000 CAC AGO CTO OC-3 (FRAG (SEQ. ID NO: 1) 5'-AA A C TGA AT GA 000 C G CAT G C 000 CAC AG O CTG GC-3' (FRAG 90) (SEQ. ID NO: 1) 5'-A AC TA AT GA GG COO CAT GGC GG CAC AGG CTO GGC-3 (FRAG 1) (SEQ. ID NO: 2) TA GAT GA 000 COO CAT GC GGG CAC AGO CTG OC-3 (FRAG 1) (SEQ. ID NO: 2) TA AT OA GO CG CAT GC 000 CAC AGO CTG GGC-3 (FRAG 1) (SEQ. ID NO: 2) TGA AT GA 000 COO CAT GC 000 CAC AGO CTO GC-3 (FRAG 1) (SEQ. ID NO: 2) AT GA 000 CGO CAT GC GOO CAC AGO CTG GC-3' (FRAG 1) (SEQ. ID NO: 2) 5'-TA AT OGA 000 CGG CAT GOC GO CAC AGG CTO GOC-3' (FRAG 1) (SEQ. ID NO: 2) 45 5'-A GAT GA 000 CG CAT GC GG CAC AGO CTG GGC-3 (FRAG 1) (SEQ. ID NO: 2) AT GA 000 COO CAT GC GO CAC AGO CTO OC-3' (FRAG 1) (SEQ. ID NO: 2) GA 000 CG CAT OC 000 CAC AGO CTO GGC-3' (FRAG 1) (SEQ. ID NO: 2) GA GO CG CAT GC 000 CAC AGO CTO GC-3 (FRAG 1) (SEQ. ID NO: 2) 5'-T GA 000 COO CAT GC 000 CAC AGO CTO OC-3 (FRAO 2) (SEQ. ID NO: 3) 000 COO CAT GC 000 CAC AGO CTO OC-3' (FRAG 2) (SEQ. ID NO: 3) 000 COO CAT GC 000 CAC AG CTO GC-3 (FRAO 2) (SEQ. ID NO: 3) 00 CG CAT GC 000 CAC AOO CTG OC-3 (FRAO 2) (SEQ. ID NO: 3) 5-000 CG CAT OC 000 CAC AGO CTG GC-3' (FRAO 2) (SEQ. ID NO: 3) 5-GO COO CAT GC GO CAC AGO CTG GGC-3 (FRAG 2) (SEQ. ID NO: 3) 5'-G CO CAT GC GG CAC AGO CTG GGC-3 (FRAG 2) (SEQ. ID NO: 3) CAT GC 000 CAC AGO CTO GGC-3 (FRAG 2) (SEQ. ID NO: 3) CAT GC 000 CAC AGO CTG OC-3' (FRAO 2) (SEQ. ID NO: 3) GOC 000 CAC AGO CTO OOC-3' (FRAO 30) (SEQ. ID NO: H:\Gabiiela\Kecp\SpciA9395 l-98.doc 05/07/02 WO 99/13886 PCT/US98/19419 GGC 000 CAC AGG CTG GGC-3' (FRAG 3 1) (SEQ. ID NO: 41) OGC GGG CAC AGO CTG GGC-3' (FRAG 32) (SEQ. ID NO: 42) 000 CAC AGG CTG GGC-3- (FRAG 33) (SEQ. ID NO: 43) GGG CAC AGG CTG GGC-3' (FRAG 34) (SEQ. ID NO: 4) GGG CAC AGO CTG GGC-3' (FRAG 35) (SEQ. ID NO: CAC AGO CTG GGC-3' (FRAG 36) (SEQ. n) NO: 46) CAC AGG CTG GGC-3- (FRAG 37) (SEQ. ID NO: 47) CAC AGG CTG GGC-3 (FRAG 38) (SEQ. ID NO: 48) Y-CAC AGO CTG GGC-3- (FRAG 39) (SEQ. ID NO: 49) 5 '-AC AGG CTG GGC-3' (FRAG 40) (SEQ. ED NO: AGO CTG GGC-3' (FRAG 41) (SEQ. IID NO: 51) CTG GGC-3 (FRAG 42) (SEQ. ED NO: 52) GGC CTG GAA AGC TGA GAT OGA GGG CGG CAT GGC 000 CAC AGO CTG GGC-3- (FRAG 43) (SEQ. ED NO: 53) GGC CTG GAA AOC TGA GAT OGA GOG COG CAT GGC GOG CAC AGO CTG GG-3' (FRAG 44) (SEQ. ED NO: 54) 5 -GGC GGC CTG GAA AGC TGA GAT OGA 000 CGG CAT GOC GGG CAC AGO CTG G-3 (FRAG 45) (SEQ. ID NO: GGC CTG GAA AGC TGA GAT OGA G COO CAT GGC GGG CAC AGO CTG -3'(FRAG 46) (SEQ. ED NO: 56) GGC CTG GAA AGC TOA GAT GOA GGG COG CAT GGC GG CAC AGO CT-3- (FRAG 47) (SEQ. IID NO: 57) GGC CTG GAA AGC TGA OAT GGA GGO COO CAT GOC GGG CAC AOG C-3- (FRAG 48) (SEQ. IID NO: 58) GGC CTG GAA AGC TOA OAT OGA GO COG CAT GOC GOG CAC AGG (FRAG 49) (SEQ. ED NO: 59) 5--GGC GGC CTG OAA AGC TGA GAT GGA GGG COG CAT GGC GO CAC AG-3- (FRAG 50) (SEQ. ID NO: GOC CTO GAA AOC TOA OAT OGA 000 COO CAT GOC 000 CAC A-3'(FRAG 51) (SEQ. ID NO: 61) GOC CTO GAA AGC TGA OAT OGA 000 COG CAT GOC 000 CAC-3' (FRAG 52) (SEQ. ID NO: 62) GOC CTO GAA AGC TGA OAT OGA 000 COG CAT GOC 000 CA-3 (FRAG 53) (SEQ. ID NO: 63) GOC CTO GAA AOC TGA OAT OGA 000 COO CAT GOC 000 C-3' (FRAG 54) (SEQ. ID NO: 64) s'-ooG GOC CTG OAA AOC TGA OAT OGA GOG CGO CAT GOC 000 (FRAG 55) (SEQ. ID NO: GOC CTO OAA AGC TOA OAT OGA 000 COO CAT GOC 00-3 (FRAG 56) (SEQ. ID NO: 66) GOC CTO OAA AOC TOA OAT GOA 000 COO CAT GOC G-3-(FRAG 57) (SEQ. ID NO: 67) GOC CTG OAA AGC TGA OAT OGA 000 COO CAT OGC -3 (FRAG 58) (SEQ. ID NO: 68) GOC CTO GAA AGC TbA OAT OOA 000 COO CAT 00 (FRAG 59) (SEQ. rD NO: 69) 5'-GOC GOC CTG OAA AGC TGA OAT OGA OOG COO CAT G0-3' (FRAG 60) (SEQ. ID NO: GOC CTG GAA AGC TOA OAT OGA 000 COO CAT (FRAG 61) (SEQ. ID NO: 71) GOC CTG OAA AGC TOA OAT OGA 000 COO CA-3'(FRAG 62) (SEQ. ID NO: 72) GOC CTG OAA AGC TOA OAT OGA 000 CGO C-3' (FRAG 63) (SEQ. ID NO: 73) GOC CTO OAA AGC TOA OAT OGA 000 COO (FRAG 64) (SEQ. ID NO: 74) 5*-GOC GOC CTO OAA AOC TOA OAT OGA 000 CO (FRAG 65) (SEQ. ED NO: GOC CTO OAA AOC TOA OAT OGA 000 C (FRAG 66) (SEQ. ED NO: 76) GOC CTO GAA AOC TOA OAT OGA 000 (FRAG 67) (SEQ. ID NO: 77) GOC CTO GAA AOC TGA OAT OGA GO (FRAG 68) (SEQ. ID NO: 78) GOC CTO OAA AOC TOA OAT OGA G0-3- (FRAG 69) (SEQ. ID NO: 79) 5'-GGC GOC CTO OAA AOC TOA OAT OGA (FRAG 70) (SEQ. ID NO: GOC CTO OAA AOC TGA OAT 00 (FRAO 7 1) (SEQ. ID NO: 81) GOC CTO GAA AOC TOA OAT G0-3'(FRAG 72) (SEQ. ID NO: 82) GOC CTO GAA AGC TGA OAT (FRAG 73) (SEQ. ID NO: 83) GOC CTO GAA AGC TOA OA-3' (FRAG 74) (SEQ. ID NO: 84) 5'-GOC GOC CTO OAA AOC TOA 0-3' (FRAG 75) (SEQ. ID NO: GOC CTO GAA AGC TGA-3- (FRAO 76) (SEQ. ID NO: 86) GOC CTG OAA AGC TG-3' (FRAG 77) (SEQ. ID NO: 87) GOC CTG GAA AGC T-3' (FRAG 78) (SEQ. ID NO: 88) GOC CTO OAA AOC-3' (FRAO 79) (SEQ. ID NO: 89) 5 -GOC GOC CTG GAA AO-3' (FRAG 80) (SEQ. ID NO: GOC CTO GAA A-3' (FRAG 8 1) (SEQ. I1D NO: 91) GOC CTG GAA-3'(FRAG 82) (SEQ. ID NO: 92) GOC CTO OA-3'(FRAG 83) (SEQ. ID NO: 93) GOC CTG 0-3' (FRAG 84) (SEQ. ID NO: 94) 5'-OC GOC CfG OAA AOC TOA OGAT OGA 000 COO CAT GOC *GGO CAC AGO CTO OGC-3"*(FRAG 85) (SEQ.DOnNO: GOC CTG GAA AOC TOA OAT OGA 000 COO CAT GOC 000 CAC AGO CTO 00-3' (FRAO 86) (SEQ. ID NO: 96) GOC CTO OAA AGC TOA OAT OGA GO COG CAT GOC 000 CAC AGO CTG 0-3- (FRAG 87) (SEQ. ID NO: 97) GOC CTG GAA AGC TOA OAT OGA 000 COO CAT GOC GG. CAC AGO CTO (FRAG 88). (SEQ. ID NO: 98) GOC CTG GAA AGC TGA OAT OGA 000 CGO CAT GOC 000 CAC AGO CT-3- (FRAG 89) (SEQ. ID NO:9) 5'-GC OGC CTO OAA AGC TOA OAT OGA 000 COG CAT GOC 000 CAC AGO C-3- (FRAG 90) (SEQ. ID NO: 100) GOC CTO OAA AOC TOA OAT OGA 000 COO CAT GOC 000 CAC AGO (FRAG 91) (SEQ. ID NO: 101) GOC CTO GAA AOC TOA OAT OGA 000 COO CAT GOC 000 CAC AG-3' (FRAG 92) (SEQ. ID NO: 102) GOC CTO OAA AOC TOA OAT OGA 000 COO CAT GGC G00 CAC A-3' (FRAO 93) (SEQ. ID NO: 103) GOC CTO GAA AGC TOA OAT OGA 000 COO CAT GOC 000 CAC-3' (FRAG 94) (SEQ. ID NO: 104) WO 99/1 3886PC/S8199 PCT/US98/19419 GGC CTG GAA AGC TGA GAT GGA GOG COO CAT GGC 000 CA-3' (FRAG 95) (SEQ. ID NO: 105) GGC CTG GAA AOC TGA GAT GGA GG CGG CAT GGC GGG C-3' (FRAG 96) (SEQ0. ID NO: 106) GGC CTG GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG (FRAG 97) (SEQ. ID NO: 107) GGC CTG GAA AOC TGA GAT GGA GO COO CAT GGC 00-3' (FRAG 98) (SEQ. ID NO: 108) 5-OGC GOC CTO GAA AOC TGA OAT OGA 000 COG CAT GOC G-3- (FRAG 99) (SEQ. ID NO: 109) GGC CTG GAA AGC TGA OAT GGA GGG CGG CAT GGC (FRAG 100) (SEQ. ID NO: 110) GOC CTG, GAA AGC TGA GAT OGA 000 COO CAT OG (FRAG 101) (SEQ. ID NO: 111) GGC. CTG GAA AGC TOA GAT GGA GO CGG CAT G0-3- (FRAG 102) (SEQ. ID NO: 112) GOC CTO GAA AOC TGA OAT GGA GO CGO CAT (FRAG 103) (SEQ. ID NO: 113) 5'-OC GOC CTG GAA AOC TOA OAT OGA 000 CGG CA-3- (FRAG 104) (SEQ. ID NO: 114) GGC CTO OAA AGC TGA OAT GGA GOG COG C-3- (FRAG 105) (SEQ. ID NO: 115) GOC CTG OAA AOC TGA OAT OGA 000 COO (FRAO 106) (SEQ. ED NO: 116) GOC CTO GAA AOC TGA OAT OGA 000 CO (FRAG 107) (SEQ. ID NO: 117) GGC CTG GAA AGC TGA OAT OGA 000 C -3T (FRAG 108) (SEQ. ID NO: 118) 5'-OC GOC CTO OAA AOC TOA OAT OGA 000 (FRAG 109) (SEQ. ID NO: 119) GOC CTO OAA AGC TGA GAT OGA 00 (FRAG 110) (SEQ. ID NO: 120) GOC CTG GAA AGC TOA OAT OGA 0 (FRAG I 11) (SEQ. MD NO: 121) GC CTO GAA AGC TOA OAT OGA (FRAG 112) (SEQ. ID NO: 122) GOC CTO OAA AOC TGA OAT 00 (FRAG 113) (SEQ. ID NO: 123) 5'-OC GOC CTO OAA AGC TOA OAT 0 (FRAG 114) (SEQ. ID NO: 124) GOC CTG GAA AOC TGA OAT (FRAG 115) (SEQ. ID NO: 125) GOC CTG OAA AOC TOA OA-3' (FRAG 116) (SEQ. ID NO: 126) GOC CTG OAA AOC TOA 0-3' (FRAG 117) (SEQ. MD NO: 127) GOC CTO OAA AOC TOA-3' (FRAG 118) (SEQ. ID NO: 128) 5'-C GOC CTG GAA AOC TG-3' (FRAG 119) (SEQ. ID NO: 129) GGC CTO OAA AGC T-3- (FRAG 120) (SEQ. ID NO: 130) GOC CTO GAA AOC-3' (FRAG 12 1) (SEQ. ID NO: 131) GOC CTG OAA AO-3' (FRAG 122) (SEQ. ID NO: 132) GOC CTG GAA A-3' (FRAG 123) (SEQ. ID NO: 133) 5'-OC GOC CTO OAA-3' (FRAG 124) (SEQ. ID NO: 134) GOC CTO OA-3' (FRAG 125) (SEQ. ID NO: 135) GOC CTO GAA AOC TOA OAT OGA 000 COG CAT GOC 000 CAC AGO CTG OOC-3' (FRAG 126) (SEQ. ID NO: 136) GOC Cr0 GAA AOC TOA OAT OGA 000 COG CAT GOC 000 CAC AGO CTG 00-3' (FRAG 127) (SEQ. ID NO: 137) GOC CTO GAA AOC TOA OAT OGA 000 COO CAT GOC 000 CAC AGO CTO 0-3' (FRAG 128) (SEQ. ID NO: 138) 5'-C GOC CTG GAA AOC TOA OAT OGA 000 COO CAT GOC 000 CAC AGO CTG (FRAG 129) (SEQ. ID NO: 139) GOC CTO OAA AOC TOA OAT OGA 000 COG CAT GOC 000 CAC AGO CT-3' (FRAG 130) (SEQ. ID NO: 140) GOC CTO GAA AOC TGA OAT OGA 000 COO CAT GOC 000 CAC AGO C-3' (FRAG 131) (SEQ. ED NO: 141) GOC CTO OAA AOC TOA OAT OGA 000 COG CAT GOC 000 CAC AGO (FRAG 132) (SEQ. ID NO: 142) GOC CTG GAA AGC TOA OAT OGA 000 COG CAT GOC 000 CAC AO-3' (FRAG 133) (SEQ. MD NO: 143) 5'-C GOC CTO GAA AOC TOA OAT OGA 000 COO CAT GOC 000 CAC A-3' (FRAG 134) (SEQ. ED NO: 144) GOC CTO OAA AOC TOA OAT OGA 000 COO CAT OOC 000 CAC-3' (FRAG 135) (SEQ. ID NO: 145) GOC CTG GAA AGC TOA OAT OGA 000 COO CAT GOC 000 CA-3- (FRAG 136) (SEQ. ID NO: 146) GOC CTO OAA AOC TOA OAT OGA 000 COO CAT GOC 000 C-3- (FRAG 137) (SEQ. ID NO: 147) GOC CTG GAA AGC TGA OAT OGA 000 COO CAT GOC 000 (FRAG 138) (SEQ. ID NO: 148) 5'-C GOC CTG GAA AGC TGA OAT OGA 000 COG CAT GOC 00-3' (FRAG 139) (SEQ. ID NO: 149) GOC CT0 GAA AOC TOA OAT OGA 000 COG CAT GOC 0-3' (FRAG 140) (SEQ. ID NO: 150) GOC CTO GAA AOC TOA OAT OGA 000 COG CAT GOC (FRAG 141) (SEQ. 113 NO: 151) GOC CTO GAA AOC TGA OAT OGA 000 COG CAT 00 (FRAG 142) (SEQ. ID NO: 152) GOC CTO GAA AOC TGA OAT OGA 000 COG CAT 0 (FRA 143) (SEQ. ED NO: 153) 5'-C GOC Cr0 OAA AOC TGA OAT OGA 000 COO CAT (FRAG 144) (SEQ. ID NO: 154) GOC Cr0 OAA AGC TOA OAT OGA 000 COO CA-3' (FRAG 145) (SEQ. IID NO: 155) GOC Cr0 GAA AOC TGA OAT OGA 000 COG C-3- (FRAG 146) (SEQ. ED NO: 156) GOC Cr0 GAA AGC TOA OAT OGA 000 COO (FRAG 147) .(SEQ. ID NO: 157) GOC CTO GAA AGC TOA OAT OGA 000 CO (FRAG 148) (SEQ. tD NO: 158) 5'-C GOC CTO OGAA AGC TOA OAT OGA 000 C (FRAG 148) (SEQ. ID NO: 159) GOC CTG OAA AGC TGA OAT OGA 000 (FRAG 150) (SEQ. ID NO: 160) GOC CTG OAA AGC TOA OAT OGA 00 (FRAG 151) (SEQ. ID NO: 161) GGC CTG GAA AGC TOA OAT OGA 0 (FRAG 152) (SEQ. ID NO: 162) GOC CTG GAA AOC TOA OAT GGA (FRAG 153) (SEQ. ID NO: 163) 5'-C GOC CTG OAA AGC TOA OAT 00 (FRAG 154) (SEQ. ID NO: 164) GOC Cr0 OAA AOC TGA OAT G0-3' (FRAG 155) (SEQ. ID NO: 165) GOC CTO OAA AOC TGA OAT (FRAG 156) (SEQ. ED NO: 166) GOC CTO OAA AGC TOA OA-3' (FRAG 157) (SEQ. ED NO: 167) GGC CTO GAA.AGC TGA 0-3' (FRAG 158) (SEQ. ID NO: 168) 29 WO 99/13886 PCT[US98/19419 5W- 99/388 PCTUS8/ 9419 GA3(G15)(E.IDN:19 GGC CTG GAA AGC TG-3 (FRAG 15) (SEQ. ID NO: 16) GGC CTG GAA AGC T-'(FRAG 16) (SEQ. ID NO: 17) GGC CTG GAA AGC-3' (FRAG 16) (SEQ. D NO: 17) 5'-C GGC CTG GAA AG-3 (FRAG 16) (SEQ. ID NO: 17) 5-C GOC CTG OAA A-3' (FRAG 16) (SE Q. ID NO: 17) GGC CTG GAAA-3' (FRAG 16) (SEQ. ID NO: 17) -C GGC CTG G AA -3 A C T A G T G A G G C G C T G C G G C C G T G -3(FRAG 16) (SEQ ID NO 17 GGC CTG GAA AGC TOA OAT OGA GOG COG CAT GGC GGG CAC AGG CTG GG-3' (FRAG 16) (SEQ. ED NO: 17) 5' GOC CTG GAA AGC TGA GAT GGA GGG COG CAT GGC 000 CAC AGG CTG G-3- (FRAG 16) (SEQ. ID NO: 17) GGC CTG GAA AGC TGA GAT OGA GGG COG CAT GOC 000 CAC AGG CTG -3 (FRAG 16) (SEQ. ED NO: 17) GOC CTG OAA AGC TGA GAT GGA GGG COG CAT GOC GO CAC AGO, CTO-3' (FRAG 19) (SEQ. D NO: 19) GGC CTG GAA AOC TGA GAT OGA 000 COG CAT GGC GOG CAC AOG C-3 (FRAG 17) (SEQ. ID NO: 18) GOC CTG GAA AOC TGA GAT GGA 000 CGG CAT GOC GGG CAC AGO -3 (FRAG 17) (SEQ. ID NO: 18) GGC CTG OAA AGC TGA GAT GGA GGG COG CAT GOC GO CAC AGO-3' (FRAG 17) (SEQ. ED NO: 18) GOC CTG GAA AGC TGA OAT GGA GGG COG CAT GGC 000 CAC A-3 (FRAG 17) (SEQ. ID NO: 18) OGC CTG GAA AGC TOA OAT GOA 000 COO CAT GGC 000 CAC-3 (FRAG 17) (SEQ. ID NO: 18) GOC CTO OAA AGC TOA OAT OGA 000 COG CAT GOC 000 CA-3(FRAG 17) (SEQ. ID NO: 18) GOC CTO GAA AGC TOA OAT OGA 000 COG CAT GOC 000 C-3'(FRAG 17) (SEQ. ED NO: 18) OGC CTO GAA AGC TGA OAT OGA 000 COG CAT GOC 000 -3 (FRAG 17) (SEQ. ID NO: 18) 5- GOC CTG OAA AGC TOA OAT OGA 000 COO CAT GOC 000-3' (FRAG 17) (SEQ. ID NO: 18) GOC CTO GAA AGC TGA OAT OGA 000 COG CAT GOC 0-3(FRAG 19) (SEQ. ID NO: 19) GOC CTG OAA AGC TOA OAT OGA 000 COG CAT GOC -3 (FRAG 18) (SEQ. ID NO: 19) OOC CTG GAA AGC TGA OAT OOA 000 COO CAT GC (FRAG 18) (SEQ. ID NO: 19) GOC CTG GAA AGC TOA OAT OGA 000 COO CAT 0-3' (FRAG 18) (SEQ. ID NO: 19) GGC CTG GAA AGC TOA OAT OGA 000 COG CAT -3 (FRAG 18) (SEQ. M NO: 19) GGC CTO OAA AOC TGA OAT OOA 000 COG CA-3 (FRA 18) (SEQ. ID NO: 19) GOC CTG OAA AOC TOA OAT OGA 000 COG C-3(FRAG 18) (SEQ. ID NO: 19) GOC CTG GAA AGC TOA OAT OGA 000 COG -3 (FRAO 18) (SEQ. ED NO: 19) GOC CTG GAA AGC TGA OAT OGA 000 CG (FRAO 18) (SEQ. ED NO: 19) GOC CTO GAA AGC TGA OAT OGA 000 C (FRAG 18) (SEQ. ED NO: 18) GOC CTG OAA AGC TGA OAT GGA 000 -3 (FRAG 19) (SEQ. ID NO: 19) OOC CTG, OAA AGC TGA OAT OGA 000 (FRAG 19) (SEQ. D NO: GGC CTO GAA AGC TGA OAT OGA 00 (FRAG 19) (SEQ. ED NO: 355'- GOC CTG GAA AGC TOA OAT OGA 0-3 (FRAG 19) (SEQ. NO: OOC CTG GAA AGC TOA OAT G (FRAG 19) (SEQ. ID NO: GOC CTG GAA AGC TGA OAT 0-3' (FRAG 19) (SEQ. ID NO: GOC CTG GAA AOC TOA OAT (FRAG 19) (SEQ. ID NO: OGC CTG OAA AOC TGA OAT-3' (FRAG 19) (SEQ. ID NO: OOC CTG OAA AOC TOA G-3 (FRAG 19) (SEQ. ED NO: GOC CTG OAA AOC TOA -3 (FRAG 19) (SEQ. ID NO: GGC CTG GAA AOC TG-3'(FRAG 199) (SEQ. ID NO: GOC CTO OAA AGC T-3' (FRAG 200) (SEQ. ID NO: 21) OGC CTG GAA AGC-3' (FRAG 20) (SEQ. ED NO: 21) GOC CTO GAA AG-3 (FRAG 20) (SEQ. ID NO:21) GOC CTO GAA A-3' (FRAG 20) (SEQ. ID NO: 21) GC CTO GAA A-3' AG TG AG G G A G G C CA GC G G C3 (FRAG 20) (SEQ. ID NO: 2 GC CTG GAA AGC TOA OAT OGA 000 CGG CAT OGC 000 CAC AGO CTG G-3' (FRAG 20) (SEQ. ID NO: 21) GC CTG GAA AGC TGA OAT OGA 000 COO CAT GOC 000 CAC AGO CTG 0-3' (FRAG 20) (SEQ. ID NO: 21) GC CTG, GAA AGC TGA OAT OGA 000 COG CAT GOC 000 CAC AGO CTG -3 (FRAO 20) (SEQ. ED NO: 21) GC CTG OAA AGC TGA OAT OGA 000 COO CAT GOC 000 CAC AGO CT-3' (FRAG 20) (SEQ. ID NO: 21) GC CTG OAA AOC TGA OAT OGA 000 COO CAT GGC 000 CAC AGO C-3 (FRAG 20) (SEQ. ED NO: 21) GC CTG OAA AGC TOA OAT OGA 000 CGG CAT GGC 000 CAC AGO (FRAG 21) (SEQ. ED NO: 22) GC CTG GAA AGC TOA OAT GGA 000 COO CAT OOC 000 CAC AGO-3' (FRA 21) (SEQ. ID NO: 22) GC CTOG OAA AGC -TGA OAT OGA 000 COG CAT GOC 000 CAC A-3'(FRAG 21) (SEQ. ID NO: 22) GC CTG GAA AGC TOA OAT GGA 000 COO CAT GOC GOG CAC-3' (FRAO21) (SEQ. ID NO: 22) GC Cro GAA AGC TOA OAT OGA 000 COG CAT GOC 000 CA-3(FRAG 21) (SEQ. ID NO: 22) GC CTO OAA AOC TOA OAT OGA 000 COO CAT GOC 000 C-3 (FRAG 21) (SEQ. ED NO: 22) OC CTO OAA AGC TOA OAT OGA 000 CGO CAT GOC 000 (FRAG 21) (SEQ. ID NO: 22) GC CTO GAA AOC TOA OAT OGA 000 COG CAT OOC 00-' (FRAG 21) (SEQ. ID NO: 22) GCC.TO GAA AOC TGA OAT OGA 000 COO CAT GGC.G-3 (FRAG 219) (SEQ. ID NO: 229) GC CTG GAA AOC TOA OAT OGA 000 COG CAT GOC (FRAO 220) (SEQ. ID NO: 230) GC CTO OAA AOC TOA OAT OGA 000 COO CAT 00 (FRAO 221) (SEQ. ID NO: 231) GC CTO OAA AGC TOA OAT OGA 000 COO CAT 0 (FRAG 222) (SEQ. MD NO: 232) WO 99/13886 PCTIUS98/19419 WO- 99/ 3886 PCTUS8/ 9419 A GAGGCG A 3( DN:23 GC CTG GAA AGC TGA GAT GGA 000 CGG CAT-3' (FRAG 22) (SEQ. ID NO: 23) GC CTG GAA AGC TGA GAT GGA GGG COG C-3 (FRAG 22) (SEQ. ID NO: 23) GC CTG GAA AGC TGA GAT GGA GGG COO -3 (FRAG 22) (SEQ. ED NO: 23) GC CTG, GAA AGC TGA GAT OGA 000 CG -3 (FRAG 22) (SEQ. U) NO: 23) GC CTG GAA AGC TGA OAT GGA OGG CO (FRAG 22) (SEQ. ID NO: 23) GC CTG GAA AGC TGA GAT OGA GOC (FRAG 22) (SEQ. ID NO: 23) GC CTG GAA AGC TGA OAT OGA GGG (FRAG 22) (SEQ. ED NO: 23) GC CTO OAA AGC TGA GAT GGA GG (FRAO 23) (SEQ. ID NO: 24) GC CTO GAA AGC TGA OAT GGAG -3 (FRAG 23) (SEQ. ID NO: 24) GC CTG OAA AGC TGA GAT GGA (FRAG 23) (SEQ. ED NO: 24) GC CTG OAA AGC TGA GAT GG (FRAG 23) (SEQ. ED NO: 24) GC CTO GAA AOC TGA GAT (FRAG 23) (SEQ. ED NO: 24) GC CTG GAA AOC TOA GAT-3' (FRAG 23) (SEQ. ED NO: 24) GC CTO OAA AGC TGA G-3 (FRAG 23) (SEQ. ]II NO: 24) OC CTG OAA AOC TOA-3' (FRAG 23) (SEQ. ED) NO: 24) GC CTG OAA AGC TO-3' (FRAG 23) (SEQ. ED NO: 24) GC CTO OAA AOC T-3' (FRAG 23) (SEQ. ED NO: 24) GC CTG OAA AOC-3' (FRAG 24) (SEQ. ID NO: GC CTO OAA AO-3' (FRAG 24) (SEQ. ID NO: C CTO AA AOCT AG TG G G A G G A G T G-3' (FRAG 24) (SEQ. ED NO: 25 C CTO, OAA AGC TOA OAT GG A 000 COO CAT GOC 000 CAC AGO CTO OO-3' (FRAG 24) (SEQ. ED NO: C CTO OAA AOC TGA OAT OGA 000 COO CAT GOC 000 CAC AGO CTO 0-3' (FRAG 24) (SEQ. ED NO: C CTG OAA AOC TGA OAT OGA 000 COO CAT GOC 000 CAC AGO CTO (FRAG 24) (SEQ. ID NO: C CTO OAA AOC TOA OAT OGA 000 COO CAT GOC 000 CAC AGO CTG-3' (FRAG 24) (SEQ. ID NO: C CTO OAA AGC TOA OAT OGA 000 COO CAT GOC 000 CAC AGO C-3' (FRAG 24) (SEQ. ID NO: C CTO GAA AOC TOA OAT OGA 000 COO CAT GOC 000 CAC AGO -3 (FRAG 24) (SEQ. ID NO: C CTO GAA AGC TOA OAT OGA 000 COO CAT GOC 000 CAC AGO-3' (FRAG 24) (SEQ. ID NO: C CTO OAA AOC TOA OAT OGA 000 COO CAT GOC 000 CAC A-3' (FRAG 25) (SEQ. ID NO: 26) C CTG OAA AOC TOA OAT OGA 000 COO CAT GOC 000 CAC-3' (FRAG 25) (SEQ. ID NO: 26) C CTO GAA AOC TOA OAT OGA 000 COO CAT GOC 000 CA-3' (FRAO 25) (SEQ. ID NO: 26) C CTG GAA AOC TGA OAT OGA 000 COO CAT GOC 000 C-3 (FRAG 25) (SEQ. ID NO: 26) C CTO, OAA AOC TOA OAT OGA 000 COG CAT OOC 000 -3 (FRAG 25) (SEQ. ED NO: 26) C CTO GAA AOC TGA OAT OGA 000 COG CAT GOC 000-3' (FRAG 25) (SEQ. ID NO: 26) C CTG OAA AOC TGA OAT OOA 000 COO CAT GOC 0-3 (FRAG 25) (SEQ. ID NO: 26) C CTG0 GAA AOC TOA OAT OGA 000 COO CAT OOC -3 (FRAG 25) (SEQ. ID NO: 26) C CTG, OAA AOC TOA OAT OGA 000 COO CAT GOC (FRAG 25) (SEQ. ED NO: 26) C CTO OAA AOC TOA OAT OGA 000 COO CAT 00-3' (FRAG 25) (SEQ. ID NO: 26) C CTO, OAA AOC TOA OAT GGA 000 COG CAT (FRAG 26) (SEQ. ID NO: 27) C CTG OAA AOC TOA OAT OGA 000 COO CAT-3' (FRAG 26) (SEQ. ID NO: 27) C CTO OAA AGC TGA OAT OGA 000 COO C-3 (FRAG 26) (SEQ. ED NO: 27) C CTO OAA AOC TOA OAT OGA 000 COO (FRAO 26) (SEQ. ED NO: 27) C CTO, OAA AOC TOA OAT OGA 000 COO (FRAG 26) (SEQ. I) NO: 27) C CTO, GAA AOC TOA OAT OOA 000 CO (FRAO 26) (SEQ. ID NO: 27) C Cr0 OAA AOC TOA OAT GGA 000 (FRAG 26) (SEQ. ID NO: 27) C CTG OAA AOC TOA OAT OGA 000 (FRA O 26) (SEQ. ID NO: 27) C CTO, OAA AOC TOA OAT OGA 00 (FRAG 26) (SEQ. ID NO: 27) C CTO OAA AOC TOA OAT GGA0 (FRAG 26) (SEQ. D NO: 27) C CTO OAA AGC TGA OAT GA (FRAG 27) (SEQ. ED NO: 28) C CTO OAA AGC TGA OAT 00-3' (FRAG 27) (SEQ. ED NO: 28) C CTO OAA AOC TOA OAT0 (FRAG 27) (SEQ. ED NO: 28) C CTO OAA AOC TOA OAT-3' (FRAO 27) (SEQ. ED NO: 28) C CTO GAA AOC TOA G-3' (FRAG 27) (SEQ. ID NO: 28) C CTO OAA AOC TOA-3' (FRAG 27) (SQ. ID NO: 28) C Cr0 OAA AGC TO-3' (FRAG 27) (SEQ. ID NO: 28) C CTO, OAA AOC T-3 (FRAG 27) (SEQ. ID NO: 28) C CTO OAA AOC-3' (FRAG 27) (SEQ. D NO: 28) CTG AA A C T A G TG A GG3G A G G AC A GC GG C3 (FRAG 279) (SEQ. ED NO: 289) CTO OAA AOC TOA OAT OOA 000 COO CAT OOC 000 CAC AGO CTO GO-3'(FRAG 28) (SEQ. ID NO: 29) Cr0 OAA AGC TOA OAT OGA 000 COO CAT GOC 000 CAC AGO CTO 0-3' (FRAG 28) (SEQ. ED NO: 29) CTO OAA AOC TOA OAT OOA 000 COO CAT GOC 000 CAC AGO CTO (FRAG 283) (SEQ. ID NO: 293) Cr0 OAA AGC TOA GAT OGA 000 COO CAT GOC 000 CAC AGO CT-3' (FRAG 284) (SEQ. ED NO: 294) Cr0, OAA AGC TOA OAT OGA 000 COO CAT GOC 000 CAC AGO C-3' (FRAG 285) (SEQ. MD NO: 295) CTO, GAA AGC TOA OAT OGA 000 COO CAT GOC 000 CAC AOO (FRAG 286) (SEQ. ID NO: 296) WO 99/13886 PCTJUS98/1 9419 CTG GAA AGC TGA GAT GGA 000 COO CAT GGC 000 CAC AG-3' (FRAG 287) (SEQ. WD NO: 297) CTG GAA AGC TGA GAT GGA GGG CGG CAT GGC GG CAC A-3- (FRAG 288) (SEQ. ID NO: 298) CTG GAA AGC TGA GAT GGA 000 COG CAT GGC 000 CAC-3' (FRAG 289) (SEQ. ID NO: 299) CTO OAA AGC TGA GAT OGA GGG COG CAT GOC G CA-3'(FRAG 290) (SEQ. ID NO: 300) CTG GAA AGC TGA GAT OGA G CGG CAT GGC 000 C-3' (FRAG 291) (SEQ. ID NO: 301) CTG GAA AGC TGA OAT GGA GGG COO CAT GGC GG (FRAG 292) (SEQ. ID NO: 302) CTG GAA AGC TGA OAT GGA 000 CGG CAT GGC 00.3' (FRAG 293) (SEQ. ID NO: 303) CTG GAA AGC TGA GAT OGA GGG CGG CAT GGC G-3- (FRAG 294) (SEQ. ID NO: 304) CTG GAA AGC TOA GAT GGA 000 COG CAT GOC (FRAO 295) (SEQ. ED NO: 305) CTG GAA AOC TGA OAT OGA 000 COG CAT 00.-3' (FRAO 296) (SEQ. IOD NO: 306) CTG GAA AGC TGA OAT OOA 000 COO CAT G0-3' (FRAO 297) (SEQ. ED NO: 307) CTG GAA AGC TGA OAT OGA 000 COG CAT (FRAG 298) (SEQ. ID NO: 308) CTG GAA AOC TGA OAT GGA 000 COG CA-3' (FRAG 299) (SEQ. ED NO: 309) CTG OAA AGC TGA OAT OGA 000 COO C-3' (FRAG 300) (SEQ. ID) NO: 310) CTG GAA AGC TGA OAT OGA 000 COG (FRAG 301) (SEQ. ID NO: 311) CTG OAA AOC TGA OAT OGA 000 CO (FRAG 302) (SEQ. ID NO: 312) CTG OAA AOC TOA OAT OGA 000 C (FRAG 303) (SEQ. ID NO: 313) CTO GAA AOC TOA OAT GOA 000 (FRAG 304) (SEQ. ID NO: 314) CTO OAA AGC TGA OAT OOA 00 (FRAG 305) (SEQ. ID NO: 315) CTO GAA AOC TOA OAT OGA 0 (FRAG 306) (SEQ. ED NO: 316) CTG GAA AGC TOA OAT OGA (FRAG 307) (SEQ. ID NO: 317) CTG GAA AGC TGA OAT 00 (FRAG 308) (SEQ. ED NO: 318) CTO GAA AGC TOA OAT G0-3- (FRAG 309) (SEQ. ED NO: 319) CTG GAA AOC TGA OAT (FRAG 310) (SEQ. ID NO: 320) CTG, GAA AOC TGA GA-3' (FRAG 311) (SEQ. ID NO: 321) CTO GAA AOC TGA 0-3' (FRAG 312) (SEQ. ID NO: 322) CTO GAA AOC TGA-3' (FRAG 313) (SEQ. ID NO: 323) CTG GAA AOC TG-3' (FRAG 314) (SEQ. ID NO: 324) CTO OAA AOC T-3' (FRAG 315) (SEQ. ID NO: 325) TO GAA AOC TOA OAT OOA 000 COO CAT GOC 000 CAC AGO CTO OGC-3' (FRAG 316) (SEQ. MD NO: 326) TO OAA AGC TOA OAT OOA 000 COO CAT OOC GO CAC AGO CTO 00-3' (FRAG 317) (SEQ. ID NO: 327) TO OAA AOC TOA OAT OOA 000 COO CAT OOC 000 CAC AGO CTG 0-3' (FRAG 318) (SEQ. ID NO: 328) TO OAA AOC TOA OAT GOA 000 COO CAT OOC 000 CAC AOO CTG, (FRAO 319) (SEQ. ID NO: 329) TO OAA AOC TOA OAT OGA 000 COO CAT OOC GO CAC AGO CT-3' (FRAG 320) (SEQ. ID NO: 330) TO OAA AOC TOA OAT OGA 000 COO CAT GOC 000 CAC AGO, C-3' (FRAO, 32 1) (SEQ. ID NO: 331) TO GAA AOC TOA OAT OGA 000 COO, CAT GOC 000 CAC AOG (FRAG 322) (SEQ. ID NO: 332) TO OAA AOC TOA OAT OGA 000 COO CAT GOC 000 CAC AO-3- (FRAO 323) (SEQ. ID NO: 333) TO GAA AOC TOA OAT OGA 000 COO CAT GOC 000 CAC A-3' (FRAO 324) (SEQ. ID NO: 334) TG GAA AGC TOA OAT OOA 000 COG CAT OGC 000 CAC-3' (FRAG 325) (SEQ. ED NO: 335) TO GAA AGC TGA OAT OGA 000 COO CAT GOC 000 CA-3' (FRAG 326) (SEQ. ID NO: 336) TO OAA AOC TGA OAT GGA 000 COO CAT GOC 000 C-3' (FRAO, 327) (SEQ. ED NO: 337) TO GAA AOC TOA OAT OGA 000 COO CAT GOC 000 (FRAG 328) (SEQ. ID NO: 338) TO GAA AOC TGA OAT OGA 000 COO CAT GOC 00-3' (FRAG 329) (SEQ. ID NO: 339) TO OAA AOC TOA OAT OGA 000 COO CAT OOC 0-3' (FRAG 330) (SEQ. ID NO: 340) TO GAA AOC TOA OAT OGA 000 COO CAT OGC (FRAG 33 1) (SEQ. ID NO: 341) TO GAA AOC TGA OAT OGA 000 COO CAT 00 (FRAG 332) (SEQ. ED NO: 342) TO OAA AOC TOA OAT OOA 000 COO CAT G0-3' (FRAO 333) (SEQ. ID NO: 343) TO OAA AOC TOA OAT OGA 000 COO CAT (FRAO 334) (SEQ. InD NO: 344) TO OAA AOC TOA OAT GGA 000 COG CA-3' (FRAG 335) (SEQ. ED NO: 345) TO GAA AOC TGA OAT OGA 000 COO C-3- (FRAG 336) (SEQ. ID NO: 346) TO OAA AOC TGA OAT OGA 000 COO (FRAO 337) (SEQ. ED NO: 347) TO OAA AOC TOA OAT OGA 000 CO (FRAO 338) (SEQ. ID NO: 348) TO OAA AGC TOA OAT GOA 000 C (FRAG 339) (SEQ. ED NO: 349) TO GAA AOC TOA OAT GOA 000 (FRAO 340) (SEQ. ED NO: 350) TO OAA AOC TGA OAT OGA 00 3- (FRAO 341) (SEQ. ED NO: 351) TO OAA AGC TGA OAT OOA 0 (FRAO 342) (SEQ. ID NO: 352) TG GAA AOC TOA OAT GOA (FRAG 343) (SEQ. ID NO: 353) TO GAA AOC TOA OAT 00 (RAG 3-44) (SEQ. ID NO: 354) TO GAA AOC'TGA OAT 0 (FRAG 345) (SEQ. IIb NO: 355) TG GAA AGC TGA OAT (FRAG 346) (SEQ. ED NO: 356) TO GAA AGC TOA OA-3' (FRAG 347) (SEQ. ID NO: 357) TO OAA AGC TOA 0-3'(FRAG 348) (SEQ. ED NO: 358) TO OAA AOC TGA-3' (RAG 349) (SEQj. ID NO: 359) TO GAA AOC TG-3' (FRAG 350) (SEQ. ID NO: 360) 33 G GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG GGC-3' (FRAG 351) (SEQ. ID NO: 361) G GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG GG-3' (FRAG 352) (SEQ. ID NO: 362) G GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG G-3' (FRAG 353) (SEQ. ID NO: 363) G GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG -3'(FRAG 354) (SEQ. ID NO: 364) G GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CT-3' (FRAG 355) (SEQ. ID NO: 365) G GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG C-3' (FRAG 356) (SEQ. ID NO: 366) G GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG (FRAG 357) (SEQ. ID NO: 367) G GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AG-3'(FRAG 358) (SEQ. ID NO: 368) G GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC A-3'(FRAG 359) (SEQ. ID NO: 369) G GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC-3'(FRAG 360) (SEQ. ID NO: 370) G GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CA-3'(FRAG 361) (SEQ. ID NO: 371) G GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG C-3'(FRAG 362) (SEQ. ID NO: 372) G GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG -3'(FRAG 363) (SEQ. ID NO: 373) G GAA AGC TGA GAT GGA GGG CGG CAT GGC GG-3'(FRAG 364) (SEQ. ID NO: 374) G GAA AGC TGA GAT GGA GGG CGG CAT GGC G-3'(FRAG 365) (SEQ. ID NO: 375) G GAA AGC TGA GAT GGA GGG CGG CAT GGC -3'(FRAG 366) (SEQ. ID NO: 376) G GAA AGC TGA GAT GGA GGG CGG CAT GG (FRAG 367) (SEQ. ID NO: 377) G GAA AGC TGA GAT GGA GGG CGG CAT G (FRAG 368) (SEQ. ID NO: 378) G GAA AGC TGA GAT GGA GGG CGG CAT -3'(FRAG 369) (SEQ. ID NO: 379) G GAA AGC TGA GAT GGA GGG CGG CA-3'(FRAG 370) (SEQ. ID NO: 380) G GAA AGC TGA GAT GGA GGG CGG C-3' (FRAG 371) (SEQ. ID NO: 381) G GAA AGC TGA GAT GGA GGG CGG -3'(FRAG 372) (SEQ. ID NO: 382) G GAA AGC TGA GAT GGA GGG CG -3'(FRAG 373) (SEQ. ID NO: 383) G GAA AGC TGA GAT GGA GGG C -3'(FRAG 374) (SEQ. ID NO: 384) G GAA AGC TGA GAT GGA GGG -3'(FRAG 375) (SEQ. ID NO: 385) G GAA AGC TGA GAT GGA GG -3'(FRAG 376) (SEQ. ID NO: 386) G GAA AGC TGA GAT GGA G -3'(FRAG 377) (SEQ. ID NO: 2415) G GAA AGC TGA GAT GGA -3'(FRAG 378) (SEQ. ID NO: 388) G GAA AGC TGA GAT GG (FRAG 379) (SEQ. ID NO: 389) G GAA AGC TGA GAT G -3'(FRAG 380) (SEQ. ID NO: 390) G GAA AGC TGA GAT -3'(FRAG 381) (SEQ. ID NO: 391) G GAA AGC TGA GA-3'(FRAG 382) (SEQ. ID NO: 392) G GAA AGC TGA G-3'(FRAG 383) (SEQ. ID NO: 393) G GAA AGC TGA-3'(FRAG 384) (SEQ. ID NO: 394) GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG GGC-3'(FRAG 385) (SEQ. ID NO: 395) GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG GG-3' (FRAG 386) (SEQ. ID NO: 396) GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG G-3' (FRAG 387) (SEQ. ID NO: 397) GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG -3'(FRAG 388) (SEQ. ID NO: 398) GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CT-3'(FRAG 389) (SEQ. ID NO: 399) GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG C-3' (FRAG 390) (SEQ. ID NO: 400) GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG -3'(FRAG 391) (SEQ. ID NO: 401) GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AG-3'(FRAG 392) (SEQ. ID NO: 402) GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC A-3'(FRAG 393) (SEQ. ID NO: 403) GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC-3' (FRAG 394) (SEQ. ID NO: 2426) GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CA-3' (FRAG 395) (SEQ. ID NO: 405) GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG C-3'(FRAG 396) (SEQ. ID NO: 406) GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG -3'(FRAG 397) (SEQ. ID NO: 407) GAA AGC TGA GAT GGA GGG CGG CAT GGC GG-3'(FRAG 398) (SEQ. ID NO: 408) GAA AGC TGA GAT GGA GGG CGG CAT GGC G-3' (FRAG 399) (SEQ. ID NO: 409) 50 GAA AGC TGA GAT GGA GGG CGG CAT GGC -3'(FRAG 400) (SEQ. ID NO: 410) GAA AGC TGA GAT GGA GGG CGG CAT GG -3'(FRAG 401) (SEQ. ID NO: 411) GAA AGC TGA GAT GGA GGG CGG CAT G -3'(FRAG 402) (SEQ. ID NO: 412) GAA AGC TGA GAT GGA GGG CGG CAT -3'(FRAG 403) (SEQ. ID NO: 413) GAA AGC TGA GAT GGA GGG CGG CA-3'(FRAG 404) (SEQ. ID NO: 414) 55 GAA AGC TGA GAT GGA GGG CGG C-3'(FRAG 405) (SEQ. ID NO: 415) GAA AC TGA OAT OGA GG CG (FRAG 406) (SEQ. ID NO: 416) GAA AGC TGA GAT GGA GGG CG (FRAG 40) (SEQ. ID NO: 416) *AA AGC TGA GAT GGA GGG C (FRAG 408) (SEQ. ID NO: 418) GAA AGC TGA GAT GGA GGG C (FRAG 40) (SEQ. ID NO: 419) GAA AGC TGA GAT GGA GGG -3'(FRAG 410) (SEQ. ID NO: 4120) GAA AGC TGA GAT GGA GG -3'(FRAG 411) (SEQ. ID NO: 421) GAA AGC TGA GAT GGA G -3'(FRAG 412) (SEQ. ID NO: 422) GAA AGC TGA GAT GGA (FRAG 41) (SEQ. ID NO: 423) GAA AGC TGA GAT GG (FRAG 41) (SEQ. ID NO: 424) GAA AGC TGA GAT G (FRAG 414) (SEQ. ID NO: 424) H:\Gabriela\Keep\Speci 9395l -98.doc 05/07/02 &L S 5'- 5'- 5'- 5'- 5'- 5'- 5'- 5'- 5'- 5'- 51- 5'- 5'- 5'- 40 5'- 5'- 5'- 45 5'- 5'- 50 5'- 5'- 5'- 5'- 5'- 34 GAA AGC TGA GAT (FRAG 415) (SEQ. ID NO: 425) GAA AGC TGA GA-3' (FRAG 416) (SEQ. ID NO: 426) GAA AGC TGA G-3'(FRAG 417) (SEQ. ID NO: 427) AA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG GGC-3'(FRAG 418) (SEQ. ID NO: 428) AA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG GG-3'(FRAG 419) (SEQ. ID NO: 429) AA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG G-3' (FRAG 420) (SEQ. ID NO: 430) AA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG (FRAG 421) (SEQ. ID NO: 431) AA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CT-3'(FRAG 422) (SEQ. ID NO: 432) AA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG C-3'(FRAG 423) (SEQ. ID NO: 433) AA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG -3'(FRAG 424) (SEQ. ID NO: 434) AA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AG-3' (FRAG 425) (SEQ. ID NO: 435) AA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC A-3' (FRAG 426) (SEQ. ID NO: 436) AA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC-3'(FRAG 427) (SEQ. ID NO: 437) AA AGC TGA GAT GGA GGG CGG CAT GGC GGG CA-3'(FRAG 428) (SEQ. ID NO: 438) AA AGC TGA GAT GGA GGG CGG CAT GGC GGG C-3' (FRAG 429) (SEQ. ID NO: 439) AA AGC TGA GAT GGA GGG CGG CAT GGC GGG (FRAG 430) (SEQ. ID NO: 440) AA AGC TGA GAT GGA GGG CGG CAT GGC GG-3' (FRAG 431) (SEQ. ID NO: 441) AA AGC TGA GAT GGA GGG CGG CAT GGC G-3'(FRAG 432) (SEQ. ID NO: 442) AA AGC TGA GAT GGA GGG CGG CAT GGC -3'(FRAG 433) (SEQ. ID NO: 443) AA AGC TGA GAT GGA GGG CGG CAT GG (FRAG 434) (SEQ. ID NO: 444) AA AGC TGA GAT GGA GGG CGG CAT G -3'(FRAG 435) (SEQ. ID NO: 445) AA AGC TGA GAT GGA GGG CGG CAT -3'(FRAG 436) (SEQ. ID NO: 446) AA AGC TGA GAT GGA GGG CGG CA-3' (FRAG 437) (SEQ. ID NO: 447) AA AGC TGA GAT GGA GGG CGG C-3' (FRAG 438) (SEQ. ID NO: 448) AA AGC TGA GAT GGA GGG CGG -3'(FRAG 439) (SEQ. ID NO: 449) AA AGC TGA GAT GGA GGG CG -3'(FRAG 440) (SEQ. ID NO: 450) AA AGC TGA GAT GGA GGG C (FRAG 441) (SEQ. ID NO: 451) AA AGC TGA GAT GGA GGG -3'(FRAG 442) (SEQ. ID NO: 452) AA AGC TGA GAT GGA GG -3'(FRAG 443) (SEQ. ID NO: 453) AA AGC TGA GAT GGA G (FRAG 444) (SEQ. ID NO: 454) AA AGC TGA GAT GGA (FRAG 445) (SEQ. ID NO: 455) AA AGC TGA GAT GG -3'(FRAG 446) (SEQ. ID NO: 456) AA AGC TGA GAT G (FRAG 447) (SEQ. ID NO: 457) AA AGC TGA GAT -3'(FRAG 448) (SEQ. ID NO: 458) AA AGC TGA GA-3' (FRAG 449) (SEQ. ID NO: 459) A AGC TGA GAT GGA GGG CG G CAT GGC GGG CAC AGG CTG GGC-3'(FRAG 450) (SEQ. ID NO: 460) A AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG GG-3' (FRAG 451) (SEQ. ID NO: 2427) A AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG G-3'(FRAG 452) (SEQ. ID NO: 462) A AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG (FRAG 453) (SEQ. ID NO: 463) A AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CT-3'(FRAG 454) (SEQ. ID NO: 464) A AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG C-3'(FRAG 455) (SEQ. ID NO: 465) A AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG (FRAG 456) (SEQ. ID NO: 466) A AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AG-3' (FRAG 457) (SEQ. ID NO: 467) A AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC A-3'(FRAG 458) (SEQ. ID NO: 468) A AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC-3'(FRAG 459) (SEQ. ID NO: 469) A AGC TGA GAT GGA GGG CGG CAT GGC GGG CA-3' (FRAG 460) (SEQ. ID NO: 470) A AGC TGA GAT GGA GGG CGG CAT GGC GGG C-3' (FRAG 461) (SEQ. ID NO: 471) A AGC TGA GAT GGA GGG CGG CAT GGC GGG (FRAG 462) (SEQ. ID NO: 472) A AGC TGA GAT GGA GGG CGG CAT GGC GG-3'(FRAG 463) (SEQ. ID NO: 473) A AGC TGA GAT GGA GGG CGG CAT GGC G-3'(FRAG 464) (SEQ. ID NO: 474) A AGC TGA GAT GGA GGG CGG CAT GGC -3'(FRAG 465) (SEQ. ID NO: 475) A AGC TGA GAT GGA GGG CGG CAT GG (FRAG 466) (SEQ. ID NO: 476) A AGC TGA GAT GGA GGG CGG CAT G (FRAG 467) (SEQ. ID NO: 477) A AGC TGA GAT GGA GGG CGG CAT (FRAG 468) (SEQ. ID NO: 478) A AGC TGA GAT GGA GGG CGG CA-3'(FRAG 469) (SEQ. ID NO: 479) A AGC TGA GAT GGA GGG CGG C-3'(FRAG 470) (SEQ. ID NO: 480) A AGC TGA GAT GGA GGG CGG -3'(FRAG 471) (SEQ. ID NO: 481) A AGC TGA GAT GGA GGG CG -3'(FRAG 472) (SEQ. ID NO: 482) A AGC TGA GAT GGA GGG C (FRAG 473) (SEQ. ID NO: 483) A AGC TGA GAT GGA GGG (FRAG 474) (SEQ. ID NO: 484) A AGC TGA GAT GGA GG (FRAG 475) (SEQ. ID NO: 485) A AGC TGA GAT GGA G -3'(FRAG 476) (SEQ. ID NO: 486) A AGC TGA GAT GGA -3'(FRAG 477) (SEQ. ID NO: 487) A AGC TGA GAT GG -3'(FRAG 478) (SEQ. ID NO: 488) H:\Gabricla\Kcp\SpcciW\3951-98.doc 05/07/02 WO 99/13886 PCT/US98/19419 A AGC TGA GAT G (FRAG 479) (SEQ. ID NO: 489) A AGC TGA GAT (FRAG 480) (SEQ. ID NO: 490) AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG GGC-3' (FRAG 481) (SEQ. ID NO: 491) AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG GG-3' (FRAG 482) (SEQ. ID NO: 492) AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG G-3' (FRAG 483) (SEQ. ID NO: 493) AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG (FRAG 484) (SEQ. ID NO: 494) AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CT-3' (FRAG 485) (SEQ. ID NO: 495) AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG C-3' (FRAG 486) (SEQ. ID NO: 496) AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG (FRAG 487) (SEQ. ID NO: 497) AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AG-3' (FRAG 488) (SEQ. ID NO: 498) AGC TGA GAT GGA GGG COG CAT GGC GGG CAC A-3' (FRAG 489) (SEQ. ID NO: 499) AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC-3' (FRAG 490) (SEQ. ID NO: 500) AGC TGA GAT GGA GGG CGG CAT GGC GGG CA-3' (FRAG 491) (SEQ. ID NO: 501) AGC TGA GAT GGA GGG CGG CAT GGC GGG C-3' (FRAG 492) (SEQ. ID NO: 502) AGC TGA GAT GGA GGG CGG CAT GGC GGG (FRAG 493) (SEQ. ID NO: 503) AGC TGA GAT GGA GGG CGG CAT GGC GG-3' (FRAG 494) (SEQ. ID NO: 504) AGC TGA GAT GGA GGG CGG CAT GGC G-3' (FRAG 495) (SEQ. ID NO: 505) AGC TGA GAT GGA GGG CGG CAT GGC (FRAG 496) (SEQ. ID NO: 506) AGC TGA GAT GGA GGG CGG CAT GG (FRAG 497) (SEQ. ID NO: 507) AGC TGA GAT GGA GGG CGG CAT G (FRAG 498) (SEQ. ID NO: 508) AGC TGA GAT GGA GGG CGG CAT (FRAG 499) (SEQ. ID NO: 509) AGC TGA GAT GGA GGG CGG CA-3' (FRAG 500) (SEQ. ID NO: 510) AGC TGA GAT GGA GGG CGG C-3' (FRAG 501) (SEQ. ID NO: 511) AGC TGA GAT GGA GGG CGG (FRAG 502) (SEQ. ID NO: 512) AGC TGA GAT GGA GGG CG (FRAG 503) (SEQ. ID NO: 513) AGC TGA GAT GGA GGG C (FRAG 504) (SEQ. ID NO: 514) AGC TGA GAT GGA GGG (FRAG 505) (SEQ. ID NO: 515) AGC TGA GAT GGA GG (FRAG 506) (SEQ. ID NO: 516) AGC TGA GAT GGA G (FRAG 507) (SEQ. ID NO: 517) AGC TGA GAT GGA (FRAG 508) (SEQ. ID NO: 518) AGC TGA GAT GG (FRAG 509) (SEQ. ID NO: 519) AGC TGA GAT G (FRAG 510) (SEQ. ID NO: 520) GC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG GGC-3' (FRAG 511) (SEQ. ID NO: 521) GC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG GG-3' (FRAG 512) (SEQ. ID NO: 522) GC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG G-3' (FRAG 513) (SEQ. ID NO: 523) GC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG (FRAG 514) (SEQ. ID NO: 524) GC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CT-3' (FRAG 515) (SEQ. ID NO: 525) GC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG C-3' (FRAG 516) (SEQ. ID NO: 526) GC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG (FRAG 517) (SEQ. ID NO: 527) GC TGA GAT GGA GGG CGG CAT GGC GGG CAC AG-3' (FRAG 518) (SEQ. ID NO: 528) GC TGA GAT GGA GGG CGG CAT GGC GGG CAC A-3' (FRAG 519) (SEQ. ID NO: 529) GC TGA GAT GGA GGG CGG CAT GGC GGG CAC-3' (FRAG 520) (SEQ. ID NO: 530) GC TGA GAT GGA GGG CGG CAT GGC GGG CA-3' (FRAG 521) (SEQ. ID NO: 531) GC TGA GAT GGA GGG CGG CAT GGC GGG C-3' (FRAG 522) (SEQ. ID NO: 532) GC TGA GAT GGA GGG CGG CAT GGC GGG (FRAG 523) (SEQ. ID NO: 533) GC TGA GAT GGA GGG CGG CAT GGC GG-3' (FRAG 524) (SEQ. ID NO: 534) GC TGA GAT GGA GGG CGG CAT GGC G-3' (FRAG 525) (SEQ. ID NO: 535) OC TGA GAT GGA GGG CGG CAT GGC (FRAG 526) (SEQ. ID NO: 536) GC TGA GAT GGA GGG CGG CAT GG (FRAG 527) (SEQ. ID NO: 537) GC TGA GAT GGA GGG CGG CAT G (FRAG 528) (SEQ. ID NO: 538) GC TGA GAT GGA GGG CGG CAT (FRAG 529) (SEQ. ID NO: 539) GC TGA GAT GGA GGG CGG CA-3' (FRAG 530) (SEQ. ID NO: 540) GC TGA GAT GGA GG CGG C-3' (FRAG 531) (SEQ. ID NO: 541) GC TGA GAT GGA GGG CGG (FRAG 532) (SEQ. ID NO: 542) GC TGA GAT GGA GGG CG (FRAG 533) (SEQ. ID NO: 543) GC TGA GAT GGA GGG C (FRAG 534) (SEQ. ID NO: 544) GC TGA GAT GGA GGG (FRAG 535) (SEQ. ID NO: 545) GC TGA GAT GGA GG. (FRAG 536) (SEQ. ID NO; 546) GC TGA GAT GGA G (FRAG 537) (SEQ. ID NO: 547) GC TGA GAT GGA (FRAG 538) (SEQ. ID NO: 548) GC TGA GAT GG (FRAG 539) (SEQ. ID NO: 549) C TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG GGC-3' (FRAG 540) (SEQ. ID NO: 550) C TGA GAT GGA GG CGG CAT GGC GGG CAC AGG CTG GG-3' (FRAG 541) (SEQ. ID NO: 551) C TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG G-3' (FRAG 542) (SEQ. ID NO: 552) 5'- 5'- 5'- 5'- 5'- 5'- 5'- 5'- 40 5'- 5'- 5'- 5'- 5'- 5'- 55 5'- 5'- 5'- 5'- C TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG -3'(FRAG 543) (SEQ. ID NO: 553) C TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CT-3' (FRAG 544) (SEQ. ID NO: 554) C TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG C-3' (FRAG 545) (SEQ. ID NO: 555) C TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG (FRAG 546) (SEQ. ID NO: 556) C TGA GAT GGA GGG CGG CAT GGC GGG CAC AG-3' (FRAG 547) (SEQ. ID NO: 557) C TGA GAT GGA GGG CGG CAT GGC GGG CAC A-3'(FRAG 548) (SEQ. ID NO: 558) C TGA GAT GGA GGG CGG CAT GGC GGG CAC-3' (FRAG 549) (SEQ. ID NO: 559) C TGA GAT GGA GGG CGG CAT GGC GGG CA-3'(FRAG 550) (SEQ. ID NO: 560) C TGA GAT GGA GGG CGG CAT GGC GGG C-3'(FRAG 551) (SEQ. ID NO: 561) C TGA GAT GGA GGG CGG CAT GGC GGG -3'(FRAG 552) (SEQ. ID NO: 562) C TGA GAT GGA GGG CGG CAT GGC GG-3'(FRAG 553) (SEQ. ID NO: 563) C TGA GAT GGA GGG CGG CAT GGC G-3' (FRAG 554) (SEQ. ID NO: 564) C TGA GAT GGA GGG CGG CAT GGC -3'(FRAG 555) (SEQ. ID NO: 565) C TGA GAT GGA GGG CGG CAT GG (FRAG 556) (SEQ. ID NO: 566) C TGA GAT GGA GGG CGG CAT G -3'(FRAG 557) (SEQ. ID NO: 567) C TGA GAT GGA GGG CGG CAT (FRAG 558) (SEQ. ID NO: 568) C TGA GAT GGA GGG CGG CA-3'(FRAG 559) (SEQ. ID NO: 569) C TGA GAT GGA GGG CGG C-3' (FRAG 560) (SEQ. ID NO: 570) C TGA GAT GGA GGG CGG -3'(FRAG 561) (SEQ. ID NO: 571) C TGA GAT GGA GGG CG (FRAG 562) (SEQ. ID NO: 572) C TGA GAT GGA GGG C -3'(FRAG 563) (SEQ. ID NO: 573) C TGA GAT GGA GGG (FRAG 564) (SEQ. ID NO: 574) C TGA GAT GGA GG -3'(FRAG 565) (SEQ. ID NO: 575) C TGA GAT GGA G (FRAG 566) (SEQ. ID NO: 576) C TGA GAT GGA -3'(FRAG 567) (SEQ. ID NO: 577) TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG GGC-3' (FRAG 568) (SEQ. ID NO: 578) TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG GG-3'(FRAG 569) (SEQ. ID NO: 579) TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG G-3'(FRAG 570) (SEQ. ID NO: 580) TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG -3'(FRAG 571) (SEQ. ID NO: 581) TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CT-3' (FRAG 572) (SEQ. ID NO: 582) TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG C-3' (FRAG 573) (SEQ. ID NO: 583) TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG -3'(FRAG 574) (SEQ. ID NO: 584) TGA GAT GGA GGG CGG CAT GGC GGG CAC AG-3'(FRAG 575) (SEQ. ID NO: 585) TGA GAT GGA GGG CGG CAT GGC GGG CAC A-3'(FRAG 576) (SEQ. ID NO: 586) TGA GAT GGA GGG CGG CAT GGC GGG CAC-3' (FRAG 577) (SEQ. ID NO: 587) TGA GAT GGA GGG CGG CAT GGC GGG CA-3'(FRAG 578) (SEQ. ID NO: 588) TGA GAT GGA GGG CGG CAT GGC GGG C-3' (FRAG 579) (SEQ. ID NO: 589) TGA GAT GGA GGG CGG CAT GGC GGG (FRAG 580) (SEQ. ID NO: 590) TGA GAT GGA GGG CGG CAT GGC GG-3'(FRAG 581) (SEQ. ID NO: 591) TGA GAT GGA GGG CGG CAT GGC G-3'(FRAG 582) (SEQ. ID NO: 592) TGA GAT GGA GGG CGG CAT GGC -3'(FRAG 583) (SEQ. ID NO: 593) TGA GAT GGA GGG CGG CAT GG -3'(FRAG 584) (SEQ. ID NO: 594) TGA GAT GGA GGG CGG CAT G (FRAG 585) (SEQ. ID NO: 595) TGA GAT GGA GGG CGG CAT -3'(FRAG 586) (SEQ. ID NO: 596) TGA GAT GGA GGG CGG CA-3'(FRAG 587) (SEQ. ID NO: 597) TGA GAT GGA GGG CGG C-3'(FRAG 588) (SEQ. ID NO: 598) TGA GAT GGA GGG CGG (FRAG 589) (SEQ. ID NO: 599) TGA GAT GGA GGG CG (FRAG 590) (SEQ. ID NO: 600) TGA GAT GGA GGG C -3'(FRAG 591) (SEQ. ID NO: 601) TGA GAT GGA GGG (FRAG 592) (SEQ. ID NO: 602) TGA GAT GGA GG (FRAG 593) (SEQ. ID NO: 603) TGA GAT GGA G (FRAG 594) (SEQ. ID NO: 604) GA GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG GGC-3' (FRAG 595) (SEQ. ID NO: 605) GA GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG GG-3' (FRAG 596) (SEQ. ID NO: 606) GA GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG G-3'(FRAG 597) (SEQ. ID NO: 607) GA GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG (FRAG 598) (SEQ. ID NO: 608) GA GAT GGA GGG CGG CAT GGC GGG CAC AGG CT-3' (FRAG 599) (SEQ. ID NO: 609) GA GAT GGA GGG CGG CAT GGC GGG CAC AGG C-3'(FRAG 600) (SEQ. ID NO: 2422) GA GAT GGA GGG CGG CAT GGC GGG CAC AGG -3'(FRAG 601) (SEQ. ID NO: 611) GA GAT GGA GGG CGG CAT GGC GGG CAC AG-3'(FRAG 602) (SEQ. ID NO: 612) GA GAT GGA GGG CGG CAT GGC GGG CAC A-3' (FRAG 603) (SEQ. ID NO: 613) GA GAT GGA GGG CGG CAT GGC GGG CAC-3'(FRAG 604) (SEQ. ID NO: 614) GA GAT GGA GGG CGG CAT GGC GGG CA-3'(FRAG 605) (SEQ. ID NO: 615) GA GAT GGA GGG CGG CAT GGC GGG C-3' (FRAG 606) (SEQ. ID NO: 616) H:\Gabricla'Keep\Spec.93951-98.doc 05/07/02 1 WO 99/13886 PCT/US98/19419 GA GAT GGA GGG CGG CAT GGC GGG (FRAG 607) (SEQ. ID NO: 617) GA GAT GGA GGG CGG CAT GGC GG-3' (FRAG 608) (SEQ. ID NO: 618) GA GAT GGA GGG CGG CAT GGC G-3' (FRAG 609) (SEQ. ID NO: 619) GA GAT GGA GGG CGG CAT GGC (FRAG 610) (SEQ. ID NO: 620) GA GAT GGA GGG CGG CAT GG (FRAG 611) (SEQ. ID NO: 621) GA GAT GGA GGG CGG CAT G (FRAG 612) (SEQ. ID NO: 622) GA GAT GGA GGG CGG CAT (FRAG 613) (SEQ. ID NO: 623) GA GAT GGA GGG CGG CA-3' (FRAG 614) (SEQ. ID NO: 624) GA GAT GGA GGG CGG C-3' (FRAG 615) (SEQ. ID NO: 625) GA GAT GGA GGG CGG (FRAG 616) (SEQ. ID NO: 626) GA GAT GGA GGG CG (FRAG 617) (SEQ. ID NO: 627) GA GAT GGA GGG C (FRAG 618) (SEQ. ID NO: 628) GA GAT GGA GGG (FRAG 619) (SEQ. ID NO: 629) GA GAT GGA GG (FRAG 620) (SEQ. ID NO: 630) A GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG GGC-3' (FRAG 621) (SEQ. ID NO: 631) A GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG GG-3' (FRAG 622) (SEQ. ID NO: 632) A GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG G-3' (FRAG 623) (SEQ. ID NO: 633) A GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG (FRAG 624) (SEQ. ID NO: 634) A GAT GGA GGG CGG CAT GGC GGG CAC AGG CT-3' (FRAG 625) (SEQ. ID NO: 635) A GAT GGA GGG CGG CAT GGC GGG CAC AGG C-3' (FRAG 626) (SEQ. ID NO: 636) A GAT GGA GGG CGG CAT GGC GGG CAC AGG (FRAG 627) (SEQ. ID NO: 637) A GAT GGA GGG CGG CAT GGC GGG CAC AG-3' (FRAG 628) (SEQ. ID NO: 638) A GAT GGA GGG CGG CAT GGC GGG CAC A-3' (FRAG 629) (SEQ. ID NO: 639) A GAT GGA GGG CGG CAT GGC GGG CAC-3' (FRAG 630) (SEQ. ID NO: 640) A GAT GGA GGG CGG CAT GGC GGG CA-3' (FRAG 631) (SEQ. ID NO: 641) A GAT GGA GGG CGG CAT GGC GGG C-3' (FRAG 632) (SEQ. ID NO: 642) A GAT GGA GGG CGG CAT GGC GGG (FRAG 633) (SEQ. ID NO: 643) A GAT GGA GGG CGG CAT GGC GG-3' (FRAG 634) (SEQ. ID NO: 644) A GAT GGA GGG CGG CAT GGC G-3' (FRAG 635) (SEQ. ID NO: 645) A GAT GGA GGG CGG CAT GGC (FRAG 636) (SEQ. ID NO: 646) A GAT GGA GGG CGG CAT GG (FRAG 637) (SEQ. ID NO: 647) A GAT GGA GGG CGG CAT G (FRAG 638) (SEQ. ID NO: 648) A GAT GGA GGG CGG CAT (FRAG 639) (SEQ. ID NO: 649) A GAT GGA GGG CGG CA-3' (FRAG 640) (SEQ. ID NO: 650) A GAT GGA GGG CGG C-3' (FRAG 641) (SEQ. ID NO: 651) A GAT GGA GGG CGG (FRAG 642) (SEQ. ID NO: 652) A GAT GGA GGG CG (FRAG 643) (SEQ. ID NO: 653) A GAT GGA GGG C (FRAG 644) (SEQ. ID NO: 654) A GAT GGA GGG (FRAG 645) (SEQ. ID NO: 655) GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG GGC-3' (FRAG 646) (SEQ. ID NO: 656) GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG GG-3' (FRAG 647) (SEQ. ID NO: 657) GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG G-3' (FRAG 648) (SEQ. ID NO: 658) GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG (FRAG 6) (SEQ. ID NO: 659) GAT GGA GGG CGG CAT GGC GGG CAC AGG CT-3' (FRAG 650) (SEQ. ID NO: 660) GAT GGA GGG CGG CAT GGC GGG CAC AGG C-3' (FRAG 651) (SEQ. ID NO: 661) GAT GGA GGG CGG CAT GGC GGG CAC AGG (FRAG 652) (SEQ. ID NO: 662) GAT GGA GGG CGG CAT GGC GGG CAC AG-3' (FRAG 653) (SEQ. ID NO: 663) GAT GGA GGG CGG CAT GGC GGG CAC A-3' (FRAG 654) (SEQ. ID NO: 664) GAT GGA GGG CGG CAT GGC GGG CAC-3' (FRAG 655) (SEQ. ID NO: 665) GAT GGA GGG CGG CAT GGC GGG CA-3' (FRAG 656) (SEQ. ID NO: 666) GAT GGA GGG CGG CAT GGC GGG C-3' (FRAG 657) (SEQ. ID NO: 667) GAT GGA GGG CGG CAT GGC GGG (FRAG 658) (SEQ. ID NO: 668) GAT GGA GGG CGG CAT GGC GG-3' (FRAG 659) (SEQ. ID NO: 669) .GAT GGA GGG CGG CAT GGC G-3' (FRAG 660) (SEQ. ID NO: 670) GAT GGA GGG CGG CAT GGC (FRAG 661) (SEQ. ID NO: 671) GAT GGA GGG CGG CAT GG (FRAG 662) (SEQ. ID NO: 672) GAT GGA GGG CGG CAT G (FRAG 663) (SEQ. ID NO: 673) GAT GGA GGG CGG CAT (FRAG 664) (SEQ. ID NO: 674) GAT GGA GGG CGG CA-3' (FRAG 665) (SEQ. ID NO: 675) GAT GGA GGG CGG C-3' (FRAG 666) (SEQ. ID NO: 676) GAT GGA GGG CGG (FRAG 667) (SEQ. ID NO: 677) GAT GGA GGG CG (FRAG 668) (SEQ. ID NO: 678) GAT GGA GGG C (FRAG 669) (SEQ. ID NO: 679) AT GGA GGG CGG CAT GGC GGG CAC AGG CTG GGC-3' (FRAG 670) (SEQ. ID NO: 680) 37 WO 99/1 3886 PCT/US98/1 9419 AT GGA GGG CGG CAT GGC GGG CAC AGO CTG GG-3'(FRAG 671) (SEQ. ID NO: 681) AT GGA GGG CGG CAT GGC GGG CAC AGO CTG 0-3' (FRAG 672) (SEQ. ED NO: 682) AT OGA GO COO CAT GGC 000 CAC AGO CTG (FRAG 673) (SEQ. ED NO: 683) AT GGA GGG CGG CAT GGC 000 CAC AGG CT-3' (FRAG 674) (SEQ. ID NO: 684) AT GGA 000 COO CAT GGC 000 CAC AGO C-3' (FRAG 675) (SEIQ. ID NO: 685) AT GGA 000 CGG CAT GGC 000 CAC AGO (FRAG 676) (SEQ. ID NO: 686) AT GGA GOG CGG CAT GOC GGG CAC AG-3' (FRAG 677) (SEQ. ID NO: 687) AT GGA 000 CGG CAT GGC 000 CAC A-3' (FRAG 678) (SEQ. ID NO: 688) AT OGA GO COG CAT GGC G CAC-3- (FRAG 679) (SEQ. InD NO: 689) AT GGA GGG COG CAT GGC GOG CA-3- (FRAG 680) (SEQ. ID NO: 690) AT OGA GGG COO CAT GGC GGG C-3' (FRAG 68 1) (SEQ. ID NO: 691) AT GGA 000 COO CAT GGC 000 (FRAG 682) (SEQ. ED NO: 692) AT GGA GGG CGG CAT GGC GG-3' (FRAG 683) (SEQ. ED NO: 693) AT GGA 000 CGG CAT GGC G-3' (FRAG 684) (SEQ. ED NO: 694) AT GGA G COG CAT GGC (FRAG 685) (SEQ. ID NO: 695) AT GGA GOG CGG CAT 00 (FRAG 686) (SEQ. ID NO: 696) AT G GA 000 CGO CAT G0-3' (FRAG 687) (SEQ. ED NO: 697) AT GGA GGG CGG CAT (FRAG 688) (SEQ. IID NO: 698) AT GOA GGG COG CA-3' (FRAG 689) (SEQ. ED NO: 699) AT OGA GGG CGO C-3- (FRAG 690) (SEQ. ID NO: 700) AT OGA 000 CGG (FRAG 691) (SEQ. ED NO: 701) AT GGA GOG CG (FRAG 692) (SEQ. ED NO: 702) T GOA 000 COG CAT GOC G CAC AGO CTO GGC-3' (FRAG 693) (SEQ. ED NO: 703) T GGA GGG COG CAT GOC GOG CAC AGG CTG GG-3' (FRAG 694) (SEQ. ID NO: 704) T OGA GOG COO CAT OGC 000 CAC AGO CTG 0.3' (FRAG 695) (SEQ. ID NO: 705) T OGA 000 COO CAT GGC 000 CAC AGO CTG (FRAG 696) (SEQ. EID NO: 706) T OGA OGG COG CAT GOC 000 CAC AGO CT-3' (FRAG 697) (SEQ. H) NO: 707) T GGA 000 COG CAT GOC GGO CAC AGO C-3- (FRAG 698) (SEQ. ID NO: 708) T OGA GOG CGG CAT GOC GGG CAC AGO (FRAG 699) (SEQ. ED NO: 709) T GGA 000 COG CAT GGC 000 CAC AG-3'(FRAG 700) (SEQ. ID NO: 710) TOGGA 000 COG CAT GOC GOG CAC A-3' (FRAG 701) (SEQ. ID NO: 711) T GGA GOG COG CAT OGC 000 CAC-3' (FRAG 702) (SEQ. ED NO: 712) T OGA GOG COG CAT GOC 000 CA-3' (FRAG 703) (SEQ. ID NO: 713) T OGA GOG COG CAT GOC GO C-3' (FRAG 704) (SEQ. ED NO: 714) T OGA 000 CGG CAT GOC 000 (FRAG 705) (SEQ. ED NO: 715) T GOA GOG COG CAT GOC 00-3' (FRAG 706) (SEQ. InD NO: 716) TOGGA 000 CGG CAT GOC 0-3' (FRAG 707) (SEQ. ID NO: 717) T OGA 000 COG CAT GOC (FRAG 708) (SEQ. MD NO: 718) T OGA 000 COO CAT 00 (FRAG 709) (SEQ. ID NO: 719) TOGGA 000 COO CAT G0-3' (FRAG 710) (SEQ. ID NO: 720) TOGGA 000 COO CAT (FRAG 711) (SEQ. ID NO: 721) T GGA 000 COO CA-3' (FRAG 712) (SEQ. ID NO: 722) TOGGA 000 COG C-3'(FRAO 713) (SEQ. ID NO: 723) TOGGA 000 COG (FRAG 714) (SEQ. ID NO: 724) OGA 000 COO CAT GOC 000 CAC AGO CTG GrdC-3' (FRAO 715) (SEQ. ED NO: 725) OGA 000 COO CAT GOC 000 CAC AGO CTG 00-3' (FRAG 716) (SEQ. ID NO: 726) OGA 000 CGO CAT GOC 000 CAC AGO CTG 0-3'(FRAG 717) (SEQ. ED NO: 727) OGA 000 COO CAT GOC 000 CAC AGO CTO (FRAG 718) (SEQ. ED NO: 728) 51- OGA 000 COG CAT GOC 000 CAC AGO CT-3' (FRAG 719) (SEQ. ID NO: 729) OGA 000 COO CAT GOC 000 CAC AGO C-3'(FRAG 720) (SEQ. ID NO: 730) OGA 000 COO CAT GOC 000 CAC AGO (FRAG 721) (SEQ. ED NO: 731) OGA 000 COO CAT GOC 000 CAC AG-3' (FRAG 722) (SEQ. ED NO: 732) OGA 000 COG CAT GOC 000 CAC A-3' (FRAG 723) (SEQ. UD NO: .733) OGA 000 COG CAT GOC 000 CAC-3'(FRAG 724) (SEQ. ID NO: 734) OA 000 COG CAT GOC 000 CA-3' (FRAG 725) (SEQ. ID NO: 735).

OGA 000 COO CAT GOC 000 C-3' (FRAG 726) (SEQ. ID NO: 736) OGA 000 COO CAT OOC 000 (FRAG 727) (SEQ. ID NO: 737) OGA 000 COO CAT GOC 00-3' (FRAG 728) (SEQ. ID NO: 738) OGA 000 COG CAT OGC 0-3' (FRAG 729) (SEQ. ID NO: 739) OOA 000 COG CAT GOC (FRAG 730) (SEQ. ID NO: 740) OGA 000 COG CAT 00 (FRAG 731) (SEQ. ED NO: 741) OGA GOG COG CAT G0-3' (FRAG 732) (SEQ. ED NO: 742) 51- OGA 000 COO CAT (FRAG 733) (SEQ. ID NO: 743) OGA 000 CGG CA-3' (FRAG 734) (SEQ. ID NO: 744) 38- WO 99/13886 PCT/US98/19419 GGA GGG CGG C-3' (FRAG 735) (SEQ. ID NO: 745) GA GGG CGG CAT GGC GGG CAC AGG CTG GGC-3' (FRAG 736) (SEQ. ID NO: 746) GA GGG CGG CAT GGC GGG CAC AGG CTG GG-3' (FRAG 737) (SEQ. ID NO: 747) GA GGG CGG CAT GGC GGG CAC AGG CTG G-3' (FRAG 738) (SEQ. ID NO: 748) GA GGG CGG CAT GGC GGG CAC AGG CTG (FRAG 739) (SEQ. ID NO: 749) GA GGG CGG CAT GGC GGG CAC AGG CT-3' (FRAG 740) (SEQ. ID NO: 750) GA GGG CGG CAT GGC GGG CAC AGG C-3' (FRAG 741) (SEQ. ID NO: 751) GA GGG CGG CAT GGC GGG CAC AGG (FRAG 742) (SEQ. ID NO: 752) GA GGG CGG CAT GGC GGG CAC AG-3' (FRAG 743) (SEQ. ID NO: 753) GA GGG CGG CAT GGC GGG CAC A-3' (FRAG 744) (SEQ. ID NO: 754) GA GGG CGG CAT GGC GGG CAC-3' (FRAG 745) (SEQ. ID NO: 755) GA GGG CGG CAT GGC GGG CA-3' (FRAG 746) (SEQ. ID NO: 756) GA GGG CGG CAT GGC GGG C-3' (FRAG 747) (SEQ. ID NO: 757) GA GGG CGG CAT GGC GGG (FRAG 748) (SEQ. ID NO: 758) GA GGG CGG CAT GGC GG-3' (FRAG 749) (SEQ. ID NO: 759) GA GGG CGG CAT GGC G-3' (FRAG 750) (SEQ. ID NO: 760) GA GGG CGG CAT GGC (FRAG 751) (SEQ. ID NO: 761) GA GGG CGG CAT GG (FRAG 752) (SEQ. ID NO: 762) GA GGG CGG CAT G (FRAG 753) (SEQ. ID NO: 763) GA GGG CGG CAT (FRAG 754) (SEQ. ID NO: 764) GA GGG CGG CA-3' (FRAG 755) (SEQ. ID NO: 765) A GGG CGG CAT GGC GGG CAC AGG CTG GGC-3' (FRAG 756) (SEQ. ID NO: 766) A GGG CGG CAT GGC GGG CAC AGG CTG GG-3' (FRAG 757) (SEQ. ID NO: 767) A GGG CGG CAT GGC GGG CAC AGG CTG G-3' (FRAG 758) (SEQ. ID NO: 768) A GGG CGG CAT GGC GGG CAC AGG CTG (FRAG 759) (SEQ. ID NO: 769) A GGG CGG CAT GGC GGG CAC AGG CT-3' (FRAG 760) (SEQ. ID NO: 770) A GGG CGG CAT GGC GGG CAC AGG C-3' (FRAG 761) (SEQ. ID NO: 771) A GGG CGG CAT GGC GGG CAC AGG (FRAG 762) (SEQ. ID NO: 772) A GGG CGG CAT GGC GGG CAC AG-3' (FRAG 763) (SEQ. ID NO: 773) A GGG CGG CAT GGC GGG CAC A-3' (FRAG 764) (SEQ. ID NO: 774) A GGG CGG CAT GGC GGG CAC-3' (FRAG 765) (SEQ. ID NO: 775) A GGG CGG CAT GGC GGG CA-3' (FRAG 766) (SEQ. ID NO: 776) A GGG CGG CAT GGC GGG C-3' (FRAG 767) (SEQ. ID NO: 777) A GGG CGG CAT GGC GGG (FRAG 768) (SEQ. ID NO: 778) A GGG CGG CAT GGC GG-3' (FRAG 769) (SEQ. ID NO: 779) A GGG CGG CAT GGC G-3' (FRAG 770) (SEQ. ID NO: 780) A GGG CGG CAT GGC (FRAG 771) (SEQ. ID NO: 781) A GGG CGG CAT GG (FRAG 772) (SEQ. ID NO: 782) A GGG CGG CAT G (FRAG 773) (SEQ. ID NO: 783) A GGG CGG CAT (FRAG 774) (SEQ. ID NO: 784) GGG CGG CAT GGC GGG CAC AGG CTG GGC-3' (FRAG 775) (SEQ. ID NO: 785) GGG CGG CAT GGC GGG CAC AGG CTG GG-3' (FRAG 776) (SEQ. ID NO: 786) GGG CGG CAT GGC GGG CAC AGG CTG G-3' (FRAG 777) (SEQ. ID NO: 787) GGG CGG CAT GGC GGG CAC AGG CTG (FRAG 778) (SEQ. ID NO: 788) GGG CGG CAT GGC GGG CAC AGG CT-3' (FRAG 779) (SEQ. ID NO: 789) GGG CGG CAT GGC GGG CAC AGG C-3' (FRAG 780) (SEQ. ID NO: 790) GGG CGG CAT GGC GGG CAC AGG (FRAG 781) (SEQ. ID NO: 791) GGG CGG CAT GGC GGG CAC AG-3' (FRAG 782) (SEQ. ID NO: 792) GGG CGG CAT GGC GGG CAC A-3' (FRAG 783) (SEQ. ID NO: 793) GGG CGG CAT GGC GGG CAC-3' (FRAG 784) (SEQ. ID NO: 794) GGG CGG CAT GGC GGG CA-3' (FRAG 785) (SEQ. ID NO: 795) GGG CGG CAT GGC GGG C-3' (FRAG 786) (SEQ. ID NO: 796) GGG CGG CAT GGC GGG (FRAG 787) (SEQ. ID NO: 797) GGG CGG CAT GGC GG-3' (FRAG 788) (SEQ. ID NO: 798) GGG CGG CAT GGC G-3' (FRAG 789) (SEQ. ID NO: 799) GGG CGG CAT GGC (FRAG 790) (SEQ. ID NO: 800) GGG CGG CAT GG (FRAG 791) (SEQ. ID NO: 801) GGG CGG CAT G (FRAG 792) (SEQ. ID NO: 802) GG CGG CAT GGC GGG CAC AG G CTG GGC-3' (FRAG 793) (SEQ. ID NO: 803) GG CGG CAT GGC GGG CAC AGG CTG GG-3' (FRAG 794) (SEQ. ID NO: 804) GG CGG CAT GGC GGG CAC AGG CTG G-3' (FRAG 795) (SEQ. ID NO: 805) GG CGG CAT GGC GGG CAC AGG CTG (FRAG 796) (SEQ. ID NO: 806) GG CGG CAT GGC GGG CAC AGG CT-3' (FRAG 797) (SEQ. ID NO: 807) GG CGG CAT GGC GGG CAC AGG C-3' (FRAG 798) (SEQ. ID NO: 808) 39 WO 99/13886 PCT/US98/19419 GG CGG CAT GGC GGG CAC AGG (FRAG 799) (SEQ. ID NO: 809) GG CGG CAT GGC GGG CAC AG-3' (FRAG 800) (SEQ. ID NO: 810) GG CGG CAT GGC GGG CAC A-3' (FRAG 801) (SEQ. ID NO: 811) GG CGG CAT GGC GGG CAC-3' (FRAG 802) (SEQ. ID NO: 812) GG CGG CAT GGC GGG CA-3' (FRAG 803) (SEQ. ID NO: 813) GG CGG CAT GGC GGG C-3' (FRAG 804) (SEQ. ID NO: 814) GG CGG CAT GGC GGG (FRAG 805) (SEQ. ID NO: 815) GG.CGG CAT GGC GG-3' (FRAG 806) (SEQ. ID NO: 816) GG CGG CAT GGC G-3' (FRAG 807) (SEQ. ID NO: 817) GG CGG CAT GGC (FRAG 808) (SEQ. ID NO: 818) GG CGG CAT GG (FRAG 809) (SEQ. ID NO: 819) G CGG CAT GGC GGG CAC AGG CTG GGC-3' (FRAG 810) (SEQ. ID NO: 820) G CGG CAT GGC GGG CAC AGG CTG GG-3' (FRAG 811) (SEQ. ID NO: 821) G CGG CAT GGC GGG CAC AGG CTG G-3' (FRAG 812) (SEQ. ID NO: 822) G CGG CAT GGC GGG CAC AGG CTG (FRAG 813) (SEQ. ID NO: 823) G CGG CAT GGC GGG CAC AGG CT-3' (FRAG 814) (SEQ. ID NO: 824) G CGG CAT GGC GGG CAC AGG C-3' (FRAG 815) (SEQ. ID NO: 825) G CGG CAT GGC GGG CAC AGG (FRAG 816) (SEQ. ID NO: 826) G CGG CAT GGC GGG CAC AG-3' (FRAG 817) (SEQ. ID NO: 827) G CGG CAT GGC GGG CAC A-3' (FRAG 818) (SEQ. ID NO: 828) G CGG CAT GGC GGG CAC-3' (FRAG 819) (SEQ. ID NO: 829) G CGG CAT GGC GGG CA-3' (FRAG 820) (SEQ. ID NO: 830) G CGG CAT GGC GGG C-3' (FRAG 821) (SEQ. ID NO: 831) G CGG CAT GGC GGG (FRAG 822) (SEQ. ID NO: 832) G CGG CAT GGC GG-3' (FRAG 823) (SEQ. ID NO: 833) G CGG CAT GGC G-3' (FRAG 824) (SEQ. ID NO: 834) G CGG CAT GGC (FRAG 825) (SEQ. ID NO: 835) CGG CAT GGC GGG CAC AGG CTG GGC-3' (FRAG 826) (SEQ. ID NO: 836) CGG CAT GGC GGG CAC AGG CTG GG-3' (FRAG 827) (SEQ. ID NO: 837) CGG CAT GGC GGG CAC AGG CTG G-3' (FRAG 828) (SEQ. ID NO: 838) CGG CAT GGC GGG CAC AGG CTG (FRAG 829) (SEQ. ID NO: 839) COG CAT GGC GGG CAC AGG CT-3' (FRAG 830) (SEQ. ID NO: 840) CGG CAT GGC GGG CAC AGG C-3' (FRAG 831) (SEQ. ID NO: 841) CGG CAT GGC GGG CAC AGG (FRAG 832) (SEQ. ID NO: 842) CGG CAT GGC GGG CAC AG-3' (FRAG 833) (SEQ. ID NO: 843) CGG CAT GGC GGG CAC A-3' (FRAG 834) (SEQ. ID NO: 844) CGG CAT GGC GGG CAC-3' (FRAG 835) (SEQ. ID NO: 845) CGG CAT GGC GGG CA-3' (FRAG 836) (SEQ. ID NO: 846) CGG CAT GGC GGG C-3' (FRAG 837) (SEQ. ID NO: 847) CGG CAT GGC GGG (FRAG 838) (SEQ. ID NO: 848) CGG CAT GGC GG-3' (FRAG 839) (SEQ. ID NO: 849) CGG CAT GGC G-3' (FRAG 840) (SEQ. ID NO: 850) GG CAT GGC GGG CAC AGG C TG GGC-3' (FRAG 841) (SEQ. ID NO: 851) GG CAT GGC GGG CAC AGG CTG GG-3' (FRAG 842) (SEQ. ID NO: 852) GG CAT GGC GGG CAC AGG CTG G-3' (FRAG 843) (SEQ. ID NO: 853) GG CAT GGC GGG CAC AGG CTG (FRAG 844) (SEQ. ID NO: 854) GG CAT GGC GGG CAC AGG CT-3' (FRAG 845) (SEQ. ID NO: 855) GG CAT GGC GGG CAC AGG C-3' (FRAG 846) (SEQ. ID NO: 856) GG CAT GGC GGG CAC AGG (FRAG 847) (SEQ. ID NO: 857) GG CAT GGC GGG CAC AG-3' (FRAG 848) (SEQ. ID NO: 858) GG CAT GGC GGG CAC A-3' (FRAG 849) (SEQ. ID NO: 859) GG CAT GGC GGG CAC-3' (FRAG 850) (SEQ. ID NO: 860) GG CAT GGC GGG CA-3' (FRAG 851) (SEQ. ID NO: 861) GG CAT GGC GGG C-3' (FRAG 852) (SEQ. ID NO: 862) GG CAT GGC GGG (FRAG 853) (SEQ. ID NO: 863) GG CAT GGC GG-3' (FRAG 854) (SEQ. ID NO: 864) G CAT GGC GGG CAC AGG CTG GGC-3' (FRAG 855) (SEQ. ID NO: 865) G CAT GGC GGG CAC AGG CTG GG-3' (FRAG 856) (SEQ. ID NO: 866) G CAT GGC GGG CAC AGG CTG G-3' (FRAG 857) (SEQ. ID NO: 867) G CAT GGC GGG CAC AGG CTG (FRAG 858) (SEQ. ID NO: 868) G CAT GGC GGG CAC AGG CT-3' (FRAG 859) (SEQ. ID NO: 869) G CAT GGC GGG CAC AGG C-3' (FRAG 860) (SEQ. ID NO: 870) G CAT GGC GGG CAC AGG (FRAG 861) (SEQ. ID NO: 871) G CAT GGC GGG CAC AG-3' (FRAG 862) (SEQ. ID NO: 872) WO 99/13886 PCT/US98/I 9419 G CAT GGC GGG CAC A-3- (FRAG 863) (SEQ. ID NO: 873) 51- G CAT GGC GGG CAC-3' (FRAG 864) (SEQ. IID NO: 874) 51- G CAT GOC GO CA-3' (FRAG 865) (SEQ. ID NO: 875) 51- G CAT GGC GOG C-3' (FRAG 866) (SEQ. ID NO: 876) G CAT GGC 000 (FRAG 867) (SEQ. ID NO: 877) CAT GGC 000 CAC AGO CTG GGC-3' (FRAG 868) (SEQ. ID NO: 878) CAT GGC GOG CAC AGG CTG 00-3'(FRAG 869) (SEQ. ED NO: 879) 51- CAT GGC GGG CAC AGO CTG G-3 (FRAG 870) (SEQ. ID NO: 880) CAT GGC 000 CAC AGO CTG (FRAG 87 1) (SEQ. ED NO: 881) CAT GOC GGG CAC AGO CT-3' (FRAG 872) (SEQ. ID NO: 882) CAT GOC GGG CAC AGO C-3- (FRAG 873) (SEQ. ID NO: 883) CAT GOC 000 CAC AGO (FRAG 874) (SEQ. ED NO: 884) CAT GOC GGG CAC AG-3' (FRAG 875) (SEQ. IID NO: 885) CAT GGC GOG CAC A-3'(FRAG 876) (SEQ. ED NO: 886 CAT GOC GOG CAC-3' (FRAG 877) (SEQ. ID NO: 887) CAT GGC G CA-3' (FRAG 878) (SEQ. ID NO: 888) 51- CAT GOC GGG C-3- (FRAG 879) (SEQ. ED NO: 889) AT GOC GGG CAC AGO CTG GGC-3' (FRAG 880) (SEQ. ID NO: 890) AT GOC GGG CAC AGG CTG GG-3' (FRAG 881) (SEQ. ED NO: 891) AT GGC GGG CAC AGO CTG G-3- (FRAG 882) (SEQ. ID NO: 892) 51- AT GOC GGG CAC AGG CTG (FRAG 883) (SEQ. ED NO: 893) AT GOC GOG CAC AGO CT-3' (FRAG 884) (SEQ. ID NO: 894) 51- AT GOC GOG CAC AGO C-3' (FRAG 885) (SEQ. MD NO: 895) AT GOC 000 CAC AGO (FRAG 886) (SEQ. ED NO: 896) AT GOC 000 CAC AG-3'(FRAG 887) (SEQ. ID NO: 897) AT GGC 000 CAC A-3' (FRAG 888) (SEQ. ID NO: 898) AT GOC 000 CAC-3' (FRAG 889) (SEQ. ID NO: 899) AT GOC 000 CA-3' (FRAG 890) (SEQ. ID NO: 900) 51- T GOC GOG CAC AGO CTG GGC-3' (FRAG 891) (SEQ. DD NO: 901) 51- T GOC 000 CAC AGO CTG 00-3' (FRAG 892) (SEQ. ED NO: 902) T GOC 000 CAC AGO CTG G-3' (FRAG 893) (SEQ. ED NO: 903) T GOC 000 CAC AGO CTG (FRAG 894) (SEQ. [D NO: 904) T GOC 000 CAC AGO CT-3' (FRAG 895) (SEQ. ID NO: 905) T GOC 000 CAC AGO C-3'(FRAG 896) (SEQ. ED NO: 906) T GGC 000 CAC AGO (FRAG 897) (SEQ. ID NO: 907) T GGC GOG CAC AG-3'(FRAG 898) (SEQ. ID NO: 908) T GOC 000 CAC A-3- (FRAG 899) (SEQ. ID NO: 909) 51- T GOC 000 CAC-3' (FRAG 900) (SEQ. MI NO: 910) GOC 000 CAC AGO CTG GGC-3' (FRAG 901) (SEQ. ID NO: 911) GOC 000 CAC AGO CTO 00-3' (FRAG 902) (SEQ. ID NO: 912) GOC 000 CAC AGO CTO 0-3' (FRAG 903) (SEQ. ID NO: 913) GOC 000 CAC AGO CTG (FRAG 904) (SEQ. ID NO: 914) GOC 000 CAC AGO CT-3' (FRAG 905) (SEQ. ID NO: 915) GOC 000 CAC AGO C-3' (FRAG 906) (SEQ. ID NO: 916) GOC 000 CAC AGO (FRAG 907) (SEQ. ID NO. 917) GOC 000 CAC AO-3' (FRAG 908) (SEQ. ID NO: 918) GGC 000 CAC A-3- (FRAG 909) (SEQ. ID NO: 919) GC 000 CAC AGO CTO OGC-3' (FRAG 910) (SEQ. ID) NO: 920) GC 000 CAC AGO CTG 00-3' (FRAG 911) (SEQ. ED NO: 921) GC 000 CAC AGO CTG G-3' (FRAG 912) (SEQ. ID NO: 922) GC 000 CAC AGO CTG (FRAG 913) (SEQ. ID NO: 923) GC 000 CAC AGO CT-3' (FRAG 914) (SEQ. ED NO: 924) GC 000 CAC AGO C-3' (FRAG 915) (SEQ. ID NO: 925) GC 000 CAC AGO (FRAG 916) (SEQ. ED NO: 926) GC.GGG CAC AG-3' (FRAG 917) (SEQ. ED NO: 927) C 000 CAC AGO CTG GGC-3' (FRAG 918) (SEQ. ID NO: 928) 000 CAC AGO CTO 00-3' (FRAG 919) (SEQ. ID NO: 929) C 000 CAC AGG CTG 0-3' (FRAG 920) (SEQ. ED NO: 930) C 000 CAC AGO CTG (FRAG 921) (SEQ. ID NO: 931) C 000 CAC AGO CT-3' (FRAG 922)- (SEQ. ID NO: 932) C 000 CAC AGO C-3 (FRAG 923) (SEQ. ED NO: 933) C 000 CAC AGO (FRAG 924) (SEQ. ID NO: 934) 000 CAC AGO CTO GOC-3' (FRAG 925) (SEQ. IID NO: 935) GGG CAC AGO CTO 00-3' (FRAG 926) (SEQ. ID NO: 936) 41 42 GOG GAG AGO GTG G-3 (FRAG 927) (SEQ. ID NO: 937) GGG CAG AGG GTG (FRAG 928) (SEQ. ID NO: 938) GOG GAC AGG CT-3' (FRAG 929) (SEQ. ID NO: 939) GGG CAC AGO G-3' (FRAG 930) (SEQ. ID NO: 940) GG GAG AGG CTG GGG-3' (FRAG 931) (SEQ. ID NO: 941) GG GAG AGG CG GG-3' (FRAG 932) (SEQ. ID NO: 942) 00 GAG AGG CTG G-3' (FRAG 933) (SEQ. ID NO: 943) GG GAG AGG GTG (FRAG 934) (SEQ. ID NO: 944) GO GAG AGG GT-3' (FRAG 935) (SEQ. ID NO: 945) G GAG AGG GTG GGG-3' (FRAG 936) (SEQ. ID NO: 946) G GAG AGG CG 00-3' (FRAG 937) (SEQ. ID NO: 947) 0 GAG AGG CG G-3- (FRAG 938) (SEQ. ID NO: 948) G GAG AGO GTG (FRAG 939) (SEQ. ID NO: 949) GAG AGG GTG GGG-3' (FRAG 940) (SEQ. ID NO: 950) GAG AOG GTG GO-3- (FRAG 941) (SEQ. ID NO: 951) AGG GTG G-3' (FRAG 942) (SEQ. ID NO: 952) AGG GTG GGG-3'(FRAG 943) (SEQ. ID NO: 953) AGO GTG GG-3' (FRAG 944) (SEQ. ID NO: 954) AGG GTG GGG-3' (FRAG 945) (SEQ. ID NO: 955) 5'-TflT TGG TGC GiT TGT GTG TGT TG (FRAG 946) (SEQ. ID NO: 956) GGG GGG TGG GTG (FRAG 947) (SEQ. ID NO: 957) GGG GGT GGG GGT GTG TGG GTG GGG GT (FRAG 948) (SEQ. ID NO: 958) GGG GGG TGG GGG GGG TG (FRAG 949) (SEQ. ID NO: 959) TGG GGT TGG GTG GGG (FRAG 950) (SEQ. ID NO: 960) 5'-GiT GTG GGG GTG GGG GG (FRAG 951) (SEQ. ID NO: 961) TGG GGT TGT GGG (FRAG 952) (SEQ. ID NO: 962) GTG TGT TGT GGG (FRAG 953) (SEQ. ID NO: 963) GOT GGG TGG GT (FRAG 954) (SEQ. ID NO: 964) GGG TGG TGT GG (FRAG 955) (SEQ. ID NO: 965) 5'-GT TGG TGG TGG GGG TGG (FRAG 956) (SEQ. ID NO: 966) TGT GGT GTG GilT (FRAG 957) (SEQ. ID NO: 967) Human Adenosine A2a Receptor Anti-sense Oligonucleotide Fragments iT TGT TrlT GTG GGG GTG TGT GGT GTG TTlT Mfl TGT G GGG CTG GTG GGG GG TGT GG GGG GGG GG GTG GGT GGG GOB GGG GBT GBT GGG GBT GGG GTG OTT GilT GGG GTG GiT TGG GTG GGG TGG GGG GTG GGG GG GTG :35 GTG GGG GGT GGG GGT TG GGG GGG TGT TGG GGT GGG -GGG TGG GGG TGG GiT GTG TG GGG GilT CIT- GGT GGG GGT G TGG TGG TGG TGG TGG TGT GGG GGG G GTA GAG GGA GGA GCG GAT OAT GGG GAT GGG AGA GAG GAG AGG G GTB GBG GGB GGB GGG GBT GBT GGG GBT GGG BGB GBG GBG BGG C-3- (FRAG. NO. 1665) (SEQ. ID NO:1680) GGG GTG-3' (FRAG 1666) (SEQ. ID NO: 1681) :5'-GG GGG GG GTG-3' (FRAG 1667) (SEQ. ID NO: 1682) 40 5'-GC GGG GTG GGG GGG-3' (FRAG 1668) (SEQ. ID NO: 1683) 5'-CBGGGBOGBGGG-3- (FRAG 1669) (SEQ. ID NO: 1684) *5'-TGG iT TGT TrlT GTG GG GTG-3' (FRAG 958) (SEQ. ID NO: 968) rTT G-3- (FRAG 959) (SEQ. I NO: 969) GTG GTG GGG GG TGT GG-3' (FRAG 960) (SEQ. ID NO: 970) 5'-GGC GGG GG GTG GGT GGG-3' (FRAG 961) (SEQ. ID NO: 971) GGG GBT GBT GGG GBT GGG-3' (FRAG 962) (SEQ. ID NO: 972) 5'-GTG GTT GTT GGG GTG GilT TGG GTG-3' (FRAG 963) (SEQ. ID NO: 973) TGG GGG GTG GGG GGG-3' (FRAG 964) (SEQ. ID NO: 974) GTG GGG GGT GGG GGT TG-3' (FRAG 965) (SEQ. ID NO: 975) 5'-GGC GGG TGT TGG GGT GGG-3' (FRAG 966) (SEQ. ID NO: 976) TGG GGG TGG GiT GTG TG-3' (FRAG 967) (SEQ. ID NO: 977) GilT GTT GGT GGG GGT G-3- (FRAG 968) (SEQ. ID NO: 978) TGG TGG TGG TGG TGT GGG GGG G-3- (FRAG 969) (SEQ. ID NO: 979) 5'-OTAGAGGGAGGAGGGGATGATGGGATGGGAGAGAGGAGAGGG-3- (FRAG 970) (SEQ. ID NO: 980) 5'-GTBGBGGGBGGBGGGGBTGBTGGGGBTGGGBGBOBGBGBGOG-3 (FRAG 971) (SEQ. ID NO: 981) Human Adenosine A2b Receptor Anti-sense Oliponucleotide Fragments GGG GTG GGG GGT GT-T GOT GGG GGG GG GilT GG GCG GG GGG GGG GGG GTG GGG TGG GilT GG GGG GG GGG GGG GGG GTG GGG TGG GGG GTG GGG GGG GGG GG GGG G GGG TGG GGG GTG GGG GG TGG TGG CG GG CGG H:\Gabriela\Keep\Specd 93951I-98.doc 05/07/02 43 CGC CTC CGC CTG CCG CU- CTG GCT GGG CCC CGG GCG CCC CCT CCC CTC TTFG CTC GGG TCC CCG TG ACA GCG CGT CCT GTG TCT CCA GCA GCA TGG CCG GGC GAG CTG GGC CCC BCB GCG CGT CCT GTG TCT CCB GCB GCB TG CCG GGC CBG CTG GGC CCC-3' (FRAG. NO: 1670) (SEQ. In NO:1685) 5'-GCGCGTCCTG-3' (FRAG. NO: 1671) (SEQ. ID NO:1686) '-GCT GGG CCC CGG-3' (FRAG. NO: 1672) (SEQ. ID NO:1687) GGG GCC CCC C-3' (FRAG. NO: 1673) (SEQ. ID NO:1688) CGCCCCGC 0-3' (FRAG. NO: 1674) (SEQ. ID NO:1689) GGC GCC GTG CCG CGT CUT GGT GGC GGC GG-3' (FRAG 972) (SEQ. ID NO: 982) GUT CG 0CC CGC GCG GOG ccc GTC CGG TCG-3' (FRAG 973) (SEQ. ID NO: 983) OHT CGC GCC CG OCG GOG CCC CTC CGG TCC-3' (FRAG 974) (SEQ. ID NO: 984) CGG GTC GGG GCC CCC CGC GGC C-3- (FRAG 975) (SEQ. ID NO: 985) GCC TCG GGG CTG GGG CGC TGG TOO CCG 00-3' (FRAG 976) (SEQ. ID NO: 986) CCG CGC CTC CGC CTG CCG CUT CTG-3' (FRAG 977) (SEQ. ID NO: 987) GCT GGG CCC CGG GCG CCC CCT-3' (FRAG 978) (SEQ. ID NO: 988) CCC CTC U-G CTC GGG TCC CCG TGJ3 (FRAC 979) (SEQ. ID NO: 989) 5'-AGAGCGCGTCCTGTGTCTCCAGCAGCATGGCCGGGCCAGCTGGGCCCC-3- (FRAG 980) (SEQ. ID NO: 990) 5'-BCBGCGCGTCCTGTGTCTCCBGCBGCBTGGCCGGGCCBGCTGGGCCCC-3- (FRAG 981) (SEQ. ID NO: 991) Human Adenosine A3 Receptor Anti-sense Oligonucleotide Fragments GAG CAG TGC TGT TGT TGG GCA TCT TGC CU- CCC AGG G BCB GBG CB TGC TGT TGT TGG GCB TCT TGC CUT CCC BGG GCC CU- U C TGG TGG GGT GGT GCT GUT GUT GGG CUT TCT TCT OUT CCC BCB GBG CBG TGC TGT TGT TGG GCB TCT TGC CUT CCC BGG GCC CU- U-C TGG TGG GGT GGT GCT GT r GUI- GGG C TTT CUT CTG UTC CC (FRAG.

NO:1675) (SEQ. ID NO:1690) CB TGC-3' (FRAG. NO:1676) (SEQ. ID NO:1691) UTG GGC-3' (FRAG. NO:1677) (SEQ. ID NO:I692) 5'-TGC CUT CCC BGG G-3' (FRAG. NO:1678) (SEQ. ID NO:1693) GUT GGG CAT CU- GCC-3' (FRAG. NO:1679) (SEQ ID NO:3) GGC CTA GCT CTC GCC-3' (CRAG. NO:1680) (SEQ ID GAG CA TGC TGT TGT TOO GCA TCT TGC CUT CCC AGO G-3' (FRAG 982) (SEQ. ID NO: 992) GBG CB TGC TOT TOTTGGCB TCT TOCCU CCC BGG 0-3' (FRAG 983) (SEQ. ID NO: 993) 5'-CCC T1lT TCT GGT GGG GTG-3' (FRAG 984) (SEQ. ID NO: 994) CTG UTG U-G OGC-3' (FRAG 985) (SEQ. ID NO: 995) CUT CTO TTC CC-3' (FRAG 986) (SEQ. ID NO: 996) T17T TCT GGT GGG GTG-3' (FRAG 987) (SEQ. ID NO: 997) CTG U G UTG GOC-3' (FRAG 988) (SEQ. ID NO: 998) 5-lT CU7 CTG UTC CC-3' (FRAG 989) (SEQ. ID NO: 999) 0 Human IgE Receptor 13 Anti-sense Oligonucleotide Fragments :5'-TTTCCCCTGGGTCTTCC CTCCTGCTC1TTTTC AUTTGC TCTCCT AUTACTTUC TGTGTC CAT TrUTC AU AAC CGA GCT GT BUT TGC TCT CCT BUT BCT UTC TOT OTC CBT MIT UC BUT BBC COB GCT OT-3' (FRAG. NO:1681) (SEQ. ID NO:1694) 40 5'-CCC CTO GG-3' (FRAG. NO:1682) (SEQ. ID NO:1695) 5'-OCTCTCCTBUT-3' (FRAG. NO:1683) (SEQ. ID NO:1696) 5'-CBUTBBCCGBOCTO-3' (FRAG. NO:1684) (SEQ. ID NO:1697) 5'-lT CCC CTO GGT CUT CC-3' (FRAG 990) (SEQ. ID NO: 1000) CTO CTC liT lTT C-3- (FRAG 991) (SEQ. ID NO: 1001) ATITCTCTCCTAUTACITTCTGTGTCCATITI=CAUAACCGAGCTGT (FRAG 992) (SEQ. ID NO: 1002) BTGCTCTCCTBUTBC1TrfCTGTGTCCBrTT=CBTBBCCGBGCTGT (FRAG 993) (SEQ. ID NO: 1003) Human Fe- Receptor CD23 Antigen (IgE Receptor) Antisense Oligonucleotide Fragments 5[0-GCC TGT GTC TGT CCT CCT GCT TCG UTC CTC TCO UTC CTG CTT GOT GCC CUT 0CC G GTC CTO CTC CTC CG GCT GTO 0 GTC OTG 0CC CTG GCT CCO GCT GGIT GGG CTC CCC TOG CCT TCG CTG OCT GGC GGC GTG C GOG TCT TOC TCT GO CCT OGC TGT OGC CGT GGT TOG GGG TCT TC GCT GCC TCC GilT TOG GTG GC TCT CTO AAT AU- *GAC CU7 CCT CCA TGG COG TCC TGC U G GAT TCT CCC GA TCT CTG BBT BUT GBC CU7 CCT CCB TGG COG TCC TOC UTG GBT TCT CCC GB-3 (FRAG 1685) (SEQ. ID NO:1698) 5'-CT CCT CCT-3 (FRAG 1686) (SEQ. ID NO: 1699) OTC TGT CCT CC-3' (FRAG 1687) (SEQ. ID NO: 1700) GCC CTG OCJ3 (FRAG 1688) (SEQ. ID NO: 1701) GOT TGG 00-3' (FRAG 1689) (SEQ. ID NO: 1702) CTG BBT BU- GBC C-3- (FRAG169O) (SEQ. ID NO:1703) 5'-GCC TGT GTC TGT CCT CCT-3 (FRAG 994) (SEQ. ID NO: 1004) H;\Gabriela\I~ep\Spece03951-98.doc 05/07/02 44 TCG UTC CTC TCG UTC-3' (FRAG 995) (SEQ. ID NO:1005) C'rr GGT GCC CUT GCC G-3' (FRAG 996) (SEQ. ID NO: 1006) CTG CTC CTC CGG GCT GTG G-3' (FRAG 997) (SEQ. ID NO: 1007) OTG 0CC CTG GCT CCG OCT GOT GOG CTC CCC TGG-3' (FRAG 998) (SEQ. ID NO: 1008) 5'-CCT TCG CTG GCT OGC GGC OTG C-3' (FRAG 999) (SEQ. ID NO: 1009) TCT TOC TCT GGG CCT GOC TGT-3' (FRAG 1000) (SEQ. ID NO: 1010) COT GOT TGG GGG TCT TC-3' (FRAG 1001) (SEQ. ID NO: 1011) GCC TCC GUT TGG OTO GC (FRAG 1002) (SEQ. ID NO: 1012) CTG AAT AUT GAC CUT CCT CCA TGG COO TCC TOC UTG GAT TCT CCC GA (FRAG 1003) (SEQ. ID NO: 1013) 5'-TCT CTG BBT BUF GBC CU~ CCT CCB TOG CGG TCC TGC UTG OBT TCT CCC GB (FRAG 1004) (SEQ. ID NO: 1014) Human IUE Receptor a Subunit Anti-sense Qillonucleotide Fragments 0CC rrr CCT GOT TCT CUT OU GUT rrr 000 GU TOG CUT ACA GTA GAO TAO GGO AUT CCA TGG CAG GAG CCA TCT TCT TCA TOO ACT CC U1C AAG GAO ACC UTA GOT 1*TC TOA GGG ACT OCT AAC ACO CCA TCT GGA GC BCB OTB GBO TBO 000 BUT CCB TOG CBO OBO CCB TCT TCT TCB TOO BCT CC UTC BBO OBO BCC U-B GGT U-C TOB GOG BCT GCT BBC BCG CCB TCT 0GB GC OUT GUT T-17 OGG OlT TGO CUT 0CC TTlT CCT GOT TCT CUT BCB GTB OBO TBG GO BUT CCB TOG CBG OBG CCB TCT TCT TCB TGO BCT CC 17C BBO OBO BCC UB GOT UFC TOB GOG BCT OCT BBC BCO CCB TCT GOB OC-3' (FRAG. NO: 1691) (SEQ. ID NO: 1704) TOO BCT CC (FRAG. NO: 1692) (SEQ. ID NO:1705) TCT OGB-3' (FRAG. NO: 1693) (SEQ. ID NO: 1706) 5'-CT OCT BBC BCO-3' (FRAG. NO: 1694) (SEQ. ID NO: 1707) TilT GOO GUT TO-3' (FRAG. NO: 1695) (SEQ. ID NO:1708) TTCCTGTTCT CU rGUrGTT GGGOUTGCU-3' (FRAG. NO:1005) (SEQ. ID NO:1015) 5'-ACAOTAOAOTAOGGOAUTCCATGOCAGOAGCCATCU-CU-CATOGACTCC-3' (FRAG. NO:1006) (SEQ. ID NO:1016) AAG GAO ACC UTA GOT UTC TOA GO ACT OCT AAC ACO CCA TCT OGA GC-3'(FRAG. NO:1007) (SEQ. ID NO:1017) GTB GBG TBO 000 BUT CCB TOO CBG GBG CCB TCT TCT TCB TOG BCT CC U-C BBO OBO BCC UTB GOT UTC TOB 000-3' (FRAG. NO:1008) (SEQ. ID NO:1018) GCT BBC BCO CCB TCTGB C-3' (FRAG. NO:1009) (SEQ. ID NO:1019) O TT 000 OUTGO CT-3' (FRAG. NO:1010) (SEQ. ID NO:1020) 5'-0CC TlTCCTGTTCT CT-3' (FRAG. NO:101 1) (SEQ. ID NO:1021) 5'-BCBGTBOBOTBGOOOBU'CCBTGGCBOOBOCCBTCUTCTCBTGGBCTCC-3' (FRAG. NO:1012) (SEQ. ID NO:1022) BBG OBO BCC UTB GOT U-C TOB 000 BCT OCT BBC BCO CCB TCT GOB OC-3' (FRAG.NO:1013)(SEQ.ID NO:1023) Human 12E Receptor (Fc Epsilon R) Anti-sense Oligonucleotide Fragments .35 5'-GCC TGT OTC TOT CCT CCT OCT TCO UTC CTC TCO U-C CTG CUT GOT 0CC CUT 0CC 0 OTC CTO CTC CTC COO OCT TO 0 OTC CTC 0CC CTO OCT CCO OCT GOT 000 CTC CCC TOG CCT TCG CTO OCT GOC GOC OTG C CCC BOB BCO :BOB CCC 0GB CCO BCB GOC COT GOT TOO 000 TCT TC OCT 0CC TCC GUT TOO OTO GC OAT CTC TOA ATA U-GA CCT TCC ATG OCO OTC CTO CUT OGA OBT CTC TOB BTB UOGB CCT TCC BTG GCO OTC CTO CUT GGB-3' (FRAG:1696)(SEQ.ID NO:1709) '40 5'-TCO UTC CTC TCO-3' (FRAG: 1697) (SEQ. ID NO:2428) **5'-BOB BCO BOB C-3' (FRAG: 1698) (SEQ. ID NO: 1711) BTB UOGB-3' (FRAG: 1699) (SEQ. ID NO:1712) TOT OTC TOT CCT CCT-3' (FRAG. NO:1014) (SEQ. ID NO:1024) TCO UTC CTC TCO UTC-3' (FRAG. NO:1015)(SEQ. ID NO:1025) 5'-CTO CUT GOT 0CC CUT 0CC 0-3' (FRAG. NO:1016)(SEQ. ID NO: 1026) 5'-GTC CTO CTC CTC COG OCT OTO 0-3' (FRAG. NO:1017)(SEQ. ID NO:1027) CTC 0CC CTO OCT CCO OCT OOT 000 CTC CCC TGG-3' (FRAG. NO:1018) (SEQ. ID NO:1028) TCO CTO OCT OOC GOC OTO C-3- (FRAG. NO:1019) (SEQ. ID NO:1029) 50 5'-CCC BGB BCG BOB CCC 0GB CCO BCB-3' (FRAG. NO:1020) (SEQ. ID NO:1030) 50 5'-OOC TOOGG 000GG TCT TC-3' (FRAG. NO:1021) (SEQ. ID NO:1031) 0CC TCC OUTTGO OTO OC-3' (FRAG. NO:1022) (SEQ. ID NO:1032) 5'-GBT CTC TOB BTB UOGB CCT TCC BTO GCO OTC CTO CU- GOB-3' (FRAG. NO:1023) (SEQ. ID NO:1033) :Human Histidine Decarboxylase Anti-sense Oliponucleotide Fragments CCC UTG OOC TCT GOC TCC U-C TC TCT CTC TCC CTC TCT CTC TOT COCCTC COCCCT GOC TOCTOO GOT OOT'I GO[ C UT TOT TCT TCC UTG CTO CC 0CC CCO CTG CUT OTC T TC CTC 0 CTC TOT CCC TCT CTC TCT OTB CTC CTC BOO CTC CBT CDT CTC CCT TOG OC-3' (FRAG. NO:1700) (SEQ. ID NO:1713) H:\Gabriela\Kccp\Speci\9395I -98.doc 05/07/02 TCT GOC (FRAG. NO:1701) (SEQ. ID NO: 1714) TFG G (FRAU. NO:1702) (SEQ. ID NO: 1715) U TOT TCT TCC (FRAU. NO:1703) (SEQ. ID NO: 1716) TCT CCC TTG OOC TCT GGC TCC TTG TC-3' (FRAG. NO: 1024) (SEQ. I D NO: 1034) TCT CTC TCC CTC TCT CTC TOT (FRAG. NO:1025) (SEQ. ID NO:1035) CGC CTC CGC CCT GGC TGC TOG GOT GOT GOT OC-3' (FRAU. NO:1026) (SEQ. ID NO:1036) 1117 TOT TCT TCC TUG CTO CC-3' (FRAG. NO:1027) (SEQ. ID NO:1037) 0CC CCO CTO CT17 OTC T TC CTC 0-3- (FRAU. NO:1028) (SEQ. ID NO:1038) TOT CCC TCT CTC TCT GTB CTC CTC BGO CTC CBT CBT CTC CCT TOO GC (FRAG.NO:1029)(SEQ.ID NO:1039) Human Beta Trvptase Anti-sense Oligonucleotide Fragments OCT CCT 000 GOC CTC CTO OTC CCT CC!G GOT 0117 CCC GOC 000 CCT GOC CTG 000 CBG 000 CCG COT BOO COC GOC TCG CCB GOB COG GCB OCO CCB GCB GCB GCB OBT TCB GCB TCC TGO-3'(FRAG.NO: I704)(SEQ. ID NO: 1717) OCT CCTG000 GC CT-3' (FRAG. NO:1705) (SEQ. ID NO: 1718) BGGCC-3' (FRAG. NO:1706) (SEQ. ID NO: 1719) 5'-T GOC CTO GOG-3' (FRAU. NO:1707) (SEQ. ID NO: 1720) OCT CCT 000 GOC CTC CTG-3' (FRAG. NO:1030) (SEQ. ID NO:1040) CCT CCG GOT OUT CCC GOC-3' (FRAG. NO:1031) (SEQ. ID NO:1041) 5'-000 CCT GOC CTG 000 CBG 000 CC!G COT BGG COC GOC TCG CCB GOB COO GCB GCO CCB GCB GCB GCB GET TCB GCB TCC TGG-3' (FRAG. NO:1032) (SEQ. ID NO:1042) Human Tryptase-I Anti-sense Oligonucleotide Fragments OCT CCT 000 OGC CTC CTO OTC CCT CTO OCT 0 U7 CCC GOC CCT GOB CTG 000 CBG 000 CCOG COT BOO CGC GOC TCG CCB GOB COO GCB OCO CCB GCB GCB GCB GOC TCB GCB TCC TOG CCB COO BBT TCC-3' (FRAG. NO: 1708) (SEQ. ID NO:1721) CCT 000 GOC CTC CTO-3' (FRAG. NO:1709) (SEQ. ID NO:1722) 5'-B TCC TOO CCB COO BBT TCC -3'(FRAU. NO:1710) (SEQ. ID NO:1723) CCT C-3' (FRAG. NO: 1711) (SEQ. ID NO: 1724) OCT CCT 000 GOC CTC CTG-3' (FRAU. NO:1033) (SEQ. ID NO:1043) CCT CTO OCT 0 U- CCC OOC-3' (FRAU. NO:1034) (SEQ. ID NO:1044) 0GB CTG 000 CEO 000 CCO COT EGO COC GOC TCG CCB 0GB COG GCB OCO CCE GCB GCB GCB GOC TCB GCB TCC TOG CCB COO BBT TCC -3'(FRAU. NO: 1035) (SEQ. ID NO: 1045) Human Prostaglandin D Synthase Anti-sense Oligonucleotide Fragments OTO COG GOC CTO GTO CC CCT 000 CCT COG OTO CTO CCT OT OCO CTG CCT TCT TCT CCT GO GTC CTC 0CC 000 0CC CUT OCT 0CC CTG OCT OT 0CC CTG 000 GTC TOO 0117 COG CTO T CCC CBG CBO GEC CBG TCC! CBT CCB CEO COT OTBTG BOT BOCCBT TCT CCTOCE 0CC OEO-3' (FRAU. NO:1712) (SEQ. ID NO:1725) 5'-TTCTCCTGCB OCCOBO (FRAU.NO:1713) (SEQ.ID NO:1726) OCT 0CC CTG OCT OT-3' (FRAU. NO:1714) (SEQ. ID NO:1727) 0e TCT TCT CCT 00-3' (FRAU. NO:1715) (SEQ. ID NO:1728) 5'-GOT OTOCOGG GCCTG OTOCC-3' (FRAU. NO:1036) (SEQ. ID NO:1046) 5'-CCT 000 CCT COO OTO CTG CCT OTJ3 (FRAU. NO:1037) (SEQ. ID NO:1047) ::40 5'-OCO CTO CCT TCT TCT CCT 00-3' (FRAU. NO:1038) (SEQ. ID NO:1048) CTC 0CC 000 0CC CUT OCT 0CC CTG OCT OT-3' (FRAU. NO:1039) (SEQ. ID NO:1049) CTO 000 OTC TOO GIT COO CTG T-3' (FRAU. NO: 1040) (SEQ. ID NO: 1050) CBO CBO OBC CBG TCC CBT CCB CEO COT OTO BTO BOT BOC CBT TCT CCT GCB 0CC OBO -3' (FRAU. NO:1041) (SEQ. ID NO:1051) 0, 45 Human Cyvclooxyvgenase-2 Anti-sense Oligonucleotide Fragments 0.0.0 5'-000 COC 000 COB GCB TCO C iTI? 000 CU- UFC TCC lTr GOT T TOB OCO CCB GOB CC!G COC BCB GCB GCB 000 COC 000 COB GCE TCG CEO COG COO GCB 000-3' (FRAU. NO: 1716) (SEQ. ID NO: 1729) 0606.5'-G GCB 000 -3 (FRAU. NO: 1717) (SEQ. ID NO: 1730) *000 5'-TCCTliT GTT-3' (FRAU. NO:1718) (SEQ. ID NO:1731) 50 5'-000 COC 000 COB GCB TCG C-3- (FRAU. NO:1042) (SEQ. ID NO:1052) 5'-TTT 000 CUT 'FC TCC 'FIT GOT T-3' (FRAU. NO:1043) (SEQ. ID NO:1053) OCO CCB GOB CCG COC BCE GCB GCB 000 COC 000 COB GCB TCO CBO COG COG GCB 000 -3' (FRAU. NO:1044) (SEQ. ID NO:1054) Human Eosinophil Cationic Protein Anti-sense Oligonucleotidc Fragments H:AGabriela\Kcep\SpecdA93951I-98.doc 05/07/02 CCT TCC TGG TCT GTC TGC CBO BCB BBT T-G 0GB BOT OBB CBG 'TT TGG BBC CBT OTT TCC CBG TCT CTO BGC TOT GGC-3' (FRAG. NO: 1719) (SEQ. ID NO: 1732) TCC MT GGT T-3' (FRAG. NO:1720) (SEQ. ID NO: 1733) U-C TCC lT GGT T-3' (FRAG. NO:1721) (SEQ. ID NO:1734) GGO CGC GO COB GCB TCO C-3' (FRAG. NO:1042) (SEQ. ID NO:1052) GO CUT TC TCC TIrT OGT T-3' (FRAG. NO:1043) (SEQ. ID NO:1053) GCO CCB GOB CCG CGC BCB GCB GCB GO CGC OGG COB GCB TCG CBG CGG CGO GCB GGO -3' (FRAG. NO: 1044) (SEQ. I D NO: 1054) Human Eosinophil Derived Neurotoxin Anti-sense Oligonucleotide Fragments s'-GCC CTG CTG CTC Trr CTG CT TCC CUT GOT GOG TTG GGC C GCTr GOT TGT TCT GGG OTT C U-G CTO CCC CUT CTG TCC C TOT 'rro CTG GTO TCT GCG C CCC CBB CBO BBG BBG CBG BCB BBT UrG GOB BOT GBB CBG 'TrT TOO BBC CBT OTT TCC TGT-3'0 0 (FRAG. NO: 1722) (SEQ. ID NO: 1735) CTG T-3' (FRAG. NO:1723) (SEQ. ID NO: 1736) TT-r CTO CT-3' (FRAG. NO: 1724) (SEQ. ID NOA 737) 5'-CCC CU CTG TCC C-3' (FRAG. NO:1725) (SEQ. ID NO: 1738) GCC CTO CTG CTC TI-T CTO CT-3' (FRAG. NO:1047) (SEQ. ID NO:1055) TCC CU- GOT 000 UOr GOC C-3' (FRAG. NO:1048) (SEQ. ID NO:1056) OCT GOT TOT TCT 000 OUT C-3' (FRAG. NO: 1049) (SEQ. ID NO:2430) U-G CTO CCC CUT CTG TCC C-3' (FRAG. NO:1050) (SEQ. ID NO:1057) TOT TTO CTO OTO TCT OCO C (FRAG. NO:1051) (SEQ. ID NO:1059) CCC CBB CBO BBO BBO CBO BCB BBT UOF GOB BOT OBB CBO MT TOG BBC CBT OTT TCC TOT-3' (FRAG. NO:1052) (SEQ. ID NO:1060) Human Eosinophil Peroxidase Anti-sense Oligonucleotide Fragments CTC GGC CTO OTC CCO 0000G TCT CCT CUT OTT OTT GC UOG COC CTC CTO CTO 000 OT CC CTC TOT TCT TOT Tr17 000 GOC 000 CCC OOC COT TOT CUT 0 OTT TOO 000 T=l CCO UrG 000 TTC TCC TOG CCC 000 CCT TOC CC GOC COT OOT CCC GOC T-C OTTCCT OTC TCC OTC TCG OCT CUT CTG 000 CCT TOC OCT OTC TTlT GOT G CCG TCC BOT OBT OOT OCO OTB CUT OTC OCT GCB OCO CTC GOC CTO OTC CCO OBO BGC-31 (FRAG.NO:1726)(SEQ.ID NO:1739) GOC CTO OTC CCG G-3' (FRAG. NO: 1727) (SEQ. ID NO:1740) 5'-TOO 000 Ttr CCG T-rO-3' (FRAG. NO: 1728) (SEQ. ID NO: 1741) OTC CCO OBO BOC (FRAG. NO: 1729) (SEQ. ID NO: 1742) CTC GOC CTG GTC CCO 0-3' (FRAG. NO:1053) (SEQ. ID NO:1061) 5'-000 TCT CCT CU- OTT OTT OC-3' (FRAG. NO:1054) (SEQ. ID NO:1062) UTG COC CTC CTO CTO 000 OT CC-3' (FRAG. NO:1055) (SEQ. ID NO:1063) 5'-CTC TOT TCT TOT TilT 000 OGC-3' (FRAG. NO:1056) (SEQ. ID NO:1064) 5'-000 CCC GOC COT TOT CUT 0-3' (FRAG. NO:1057) (SEQ. ID NO:1065) TOO 000 TIlT CCO TTOG-3' (FRAG. NO:1058) (SEQ. ID NO:1066) 5'-000 U7C TCC TOO CCC 000 CCT TOC CC-3' (FRAG. NO:1059)(SEQ. ID NO:1067) 40 5'-GC COT OGT CCC OGC TTC OTT OC-3' (FRAG. NO:1060) (SEQ. ID NO:1068) 5'-CCT OTC TCC OTC TCG OCT CUT CTO-3' (FRAG. NO:1061) (SEQ. ID NO:1069) 5'-000 CCT TOC OCT OTC T GOT 0-3' (FRAG. NO:1062) (SEQ. ID NO:1070) CCO TCC BGT OBT GOT OCO 0TB CUT GTC OCT GCB OCO CTC OGC CTG OTC CCO OBO BOC (FRAG.

NO:1063) (SEQ.IDNO:1071) Human Intercellular Adhesion Molecule-i (ICAM-1) Anti-sense Oligonucleotide Fragments COO 0CC 000 OGC TOC TOO 0 OOT TOO CCC 000 OTO CCC C 0CC OCT 000 TOC CCT COT CCT CTO COG TC OTO TCT CCT GOC TCT OOT TCC CC OCT OCO CCC OTT OTC CTC TOG GOT OOC CM C OCT CCC 000 TCT GOT TCT TOT OT TOO 000 TCC CU T 000G CCT OTT OT GOC OTO OCT TOT OTO TTC GOT U7C TOC CCT OTC CTC COO COT 50 CCC COO BOC CTC CCC 000 GCB OOB TOB CU~ UOG BOO 000 BCB CBO BTO TCT 000 CBT TOC CBO OTC CTO OOB 50 BCB OBO CCC COB GCB GOB CCB GOB OTO COO GCB OCO COO 0CC 000 GOC TOC TOG OBO CCB TBO COB OGC TOB G-3' (FRAG. NO: 1730) (SEQ. ID NO: 1743) 5'-000 GOC TOC TOO 0-3' (FRAG. NO: 1731) (SEQ. ID NO:1744) OTC CTC COO COT CCC-3' (FRAG. NO: 1732) (SEQ. ID NO: 1745) CCB TBG COB GOC TOB 0-3' (FRAG. NO: 1733) (SEQ. ID NO: 1746) 555'-CTC TOO OOT GOCCUC-3' (FRAG. NO:1734) (SEQ. ID NO:1747) 0CCG000 GC TOCTGG0-3' (FRAG. NO:1064) (SEQ. ID NO:1072) H:\Gabriela\Kcp\Speci\93951 -98.doc 05/07/02 47 TGG CCC GOG GTG CCC C-3- (FRAG. NO:1065) (SEQ. ID NO:1073) GCT 000 TGC CCT CGT CCT CTG COG TC-3 (FRAG. NO:1066) (SEQ. In NO:1074) TCT CCT GG TGT GGT TCC CC-3' (FRAG. NO:1067) (SEQ. ID NO:1075) GCG CCC OTT GTG CTC TGG OGT GGC CTT C-3- (FRAG. NO:1068) (SEQ. ID NO:1076) 5'-GTCCC GGTCT GGT TCT TOTGT-3' (FRAG. NO:1069) (SEQ. ID NO:1077) TCC CiT IT GGGCT GTFGT-3 (FRAG. NO:1070) (SEQ. ID NO:1078) GTG OCT TGT GTG HGC GGT T-G-3' (FRAG. NO:1071) (SEQ. ID NO:1079) GCT GTC CTG COG GT CGC-3' (FRAG. NO:1072) (SEQ. ID NO:1080) CGG BG CTC CCC GGG GCB 0GB TGB CUT HG BOO GOG BGB CBG BTO TCT GGG CBT TGC CBO OTG CTG GOB BCB OBO CCC CGB GCB GOB CCB GGB OTG COO GCB OCO CGO GCC GGG GOG TGC TOO OBO CCB TBG GB GGC TOB (FRAG. NO:1073) (SEQ. ID NO:1081) Human Vascular Cell Adhesion Molecule 1 (VCAM-1) Anti-sense Oligonucleotide Fragments CU1 HGC TGT 'FIT TCC C GTG TG CUF TOT HG GOT TCG CU7 CCT HGC TG HGC HG C GTG TGT CTC CG TCT CCO CU 'FIT TCT TCGOTC 'FIT OHF OHT HG TCT TGCG O G BGC BBO BTB TCT BOB HGC TOO GOT GOT GTG OBT 'FIT BBBB OCT TOB OBB OCT 0GCB BBC BH7 BTC GBB BOT BTB TFIT OBO OCT GCB BOO BTC BCG BCC BTC HGC CGB GOC BHT HB BGT TG TOT CGT-3' (FRAG. NO: 1735) (SEQ. ID NO: 1748) TOT COT-3' (FRAG. NO:1736) (SEQ. ID NO:1749) HGC HG C-3- (FRAG. NO:I737) (SEQ. ID NO:1750) HSVGAM I AS 1: 5'-CGT CUT HG TOT 'FIT TCC C-3'(FRAG. NO: 1074) (SEQ. ID NO: 1082) HSVGAMIAS2: 5'-GTTG GCCTT HO GT TG-3' (FRAG. NO:1075) (SEQ. ID NO:1083) HSVGAMIAS3: 5-CH GGCTT HGT HG HGC-3 (FRAG. NO:1076) (SEQ. ID NO:1084) HSVGAMIAS4: 5-CTO TOT CTG CG TCT CG CHT 'FT TCT TC-3 (FRAG. NO:1077) (SEQ. ID NO:1085) 5'-GITOH OH HG -rTCT TCG HOG-3 (FRAG. NO:1078) (SEQ. ID NO:1086) CG BG BBO BTB TCT BOB HGC TOO GOT GOT CTC GBT 'FIT BBBB OCT TOB OBB GCT 0GCB BBC BH7 BTC GBB BOT BTB 'FIT GBO GCT CCB BOO BTC BCO BCC BTG TTG GGB GG BHr H-B BOT TOC TOT CGT-3' (FRAG.NO:1079)(SEQ.ll) NO:1087) Human Endothelial Leukocyte Adhesion Molecule (ELAM-1) Anti-sense Oligonucleotide Fragments TOB OBO CG BOB OBB BGT OTO BBO GBB TCB TGB CUT CBB OBO UrC 'FIT TCB CCC OHF CUT GOC HGC HG TOT C GT TOO GH- CTC OHF GTC CC TOT OGG CU- GTC OHT OTC GG CCC HGC GOG GG TOG TOO GG COT CCT TG CG T G 0 OH CUT GOC HGC HG TOT CG T TOO CUTCT GT OHTC CC TGT 000 CUF GTC OHT OTC CC CCC HTGG0 GOC TOO TOO OG GT CCT TG CTO CTO 0 (FRAG. NO: 1738) (SEQ. ID NO: 1751) TG CTO CTO 0-3' (FRAG. NO: 1739) (SEQ. ID NO: 1752) OTC GG-3 (FRAG. NO: 1740) (SEQ. ID NO:1753) 35 5-OHTC1 G C HGC HGr TOT C-3' (FRAG. NO:1080) (SEQ. ID NO:1088) 5'-GG TOO TOO-3' (FRAG. NO:1083) (SEQ. ID NO:1092) TOO CUT CTC OHT OTC CG-3 (FRAG. NO:1081) (SEQ. ID NO:1089) *5'-TOT 000 CUT GTC OHT OTC GC-3' (FRAG. NO:1082) (SEQ. In NO:1090) HTGG0 GG TOO TOO-3 (FRAG. NO:1083) (SEQ. ID NO:1091) 40 5'-GG GT GGT TG CG CTO 0-3- (FRAG. NO:1084) (SEQ. ID NO:1093) Human P Selectin Fragments TCT CUT TCO CIT TGT 'FIT GT CTC CTO HGC CTC GT TrU-G CG T'IT 'FT GTC CUT CUT CTC TGC 'FIT CUT HC-3' (FRAG. NO: 1741) (SEQ. ID NO: 1754) 'TrF GHT HG-3' (FRAG. NO: 1742) (SEQ. ID NO: 1755) 5'-CTC CHT H-3' (FRAG. NO:1743) (SEQ. ID NO:1756) TGT CUT TG CUT TCT 'FIT COT CTC CTO HGC CTG GHT H-3' (FRAG. NO:1085) (SEQ. ID NO:1094) CTO 'FIT 'FIT GTG CUT CU CTC TCC 'FIT GiT UGr-3' (FRAG. NO:1086) (SEQ. ID NO:1095) Human Endothelial Mono cyte Activating Factor Anti-sense Oligonucleotide Fragments TCT CUT TCO CU TGT 'FIT COT GTC CTG HGr GTG CUr HT HO GTG 'FT 'FI GTC CHT CU7 CTC TGG MFI GHT HC-3 (FRAG. NO: 1744) (SEQ. ID NO: 1754) 'FIT CU7 HG (FRAG. NO: 1745) (SEQ. ID NO: 1758) HGC CTG CUT H-3 (FRAG. NO: 1746) (SEQ. ID NO: 1759) TCT CHT TG GT TGT 'FT COT CTC CG T H CTG CUT H-3' (FRAG. NO:1087) (SEQ. ID NO:1094) CG TFT 'FIT GTC CU7 CUT CTC TGC 'FI CUT HG-3' (FRAG. NO: 1088) (SEQ. ID NO: 1095) H:\GabdieI'eep\Spcdt'93951-98.doc 05/07/02 48 Human IL3* Anti-sense Oligonucleotide Fragments TOT CU7 GU CTG GTC CUT COT GOG OCT CTG TGT CGC GTG G GTG CGO CCG TGG CC GGC GGB CCB GGB OUT GOB GCB GGB GCB GGB COG GCB GGC GGC TCB TGT YITG GBT COO CBG GBG GCB CTC-3' (FRAG.NO:1747)(SEQ.ID NO:1760) 5'-G OBG GCB CTC-3' (FRAG. NO: 1748) (SEQ. ID NO: 1761) GOG OCT CTG-3' (FRAG. NO:1749) (SEQ. ID NO:1762) HUMIL3AASI: 5'-CTC TGT CUT GUT CTO GTC CUT CGT GGG OCT CTG-3' (FRAG. NO:1089) (SEQ. ID NO:1098) HUM1L3AAS2: 5'-TGT CGC OTG G GTG CGG CCG TOG CC-3 (FRAG. NO:1090) (SEQ. ID NO:1099) GOC GOB CCB GOB GU GOB 0GCB GOB GCB GGB COG GCB GGC GGC TCB TOT UTG GBT COG CBG GBG GCB GTC (FRAG. NO: 1091) (SEQ. ID NO: 1100) Human 1L3 Receptor Anti-sense Oligonucleotide Fragments 000 OTO TCC TOO CCT TCG TOO UTC CTC UTC CTT COT 1UG CCO TCC OCO 000 0CC CCC 000 CGT GOC TOC OCT CCT 0CC CCO CCT CUT TCC COO OCT CU- OCO CTO 000 GOT OCT CC COT OTO 1TTT OCO CCC TC CTC CTG GTC OCO CU- GTC OUT U-G 000 CCG OCT UTG CCC 0CC TCC COG COC CTO 0CC COO CC U-C CTO GOC TOC GTG COC OUT CTO UTC UTC UC CTG GCT CTO 000 TOT CCT GOC CU- COT GOT TCC TCT TCC U-C OUT TOC COT CCO CG 000 CCC CG GGG CT GG TG OCT GGT GGC CCG CGT CUT TCG COO OCT CU- OCO CTO 000 GOT OCT CCC OTO TOT U-G CG CGT GCT CCT GOT CG OCT TOT GT 'TTr 00 GOC COO CUr TG CCO CCT CCC GG 0CC TOO CCC OOC CUT CCT 000 CTO COT OCO COT TCT GU- CU- CU- CCT GOC OCA OGA OAC AGO OCA 000 COA TCA OGA OCA OCO TOA 0CC AAA OGA OGA CCA TCO OGA AG CG GTG COO AAC OCA OGA CG AGO TG C GC BOO BOB GBG OG BOG GO BTG BOO BG BG OTO BG CBB BOOG BGGC BTC 000 BBC GCB GT CG GBB CG BOO BCB OBO OTO GG-3' (FRAG. NO: 1750) (SEQ. ID NO: 1763) OBO OTO CC-3' (FRAG. NO: 1751) (SEQ. ID NO: 1764) 0CC CG C-3- (FRAG. NO:1752) (SEQ. ID NO:1765) (FRAG. NO:1092) (SEQ. ID NO:110l) 5'-GCCOTGOUTCC (FRAG. NO:1093) (SEQ. ID NO:1102) 5'-TCU-CCUCO1TIC (FRAG. NO:1094) (SEQ. ID NO:1 103) (FRAG. NO:1095) (SEQ. ID NO:2420) TG OCT CCT 0CC CCG C (FRAG. NO:1096) (SEQ. ID NO:1104) 5'-CTC1J7CCGOGCTGU' (FRAG. NO:1097) (SEQ. ID NO:1106) 5'-GCGCTOGOOOGTGCTCC (FRAG. NO: 1098) (SEQ. ID NO: 1107) 5'-COTTGT1[OCCGCTGCTCCGGTGGC (FRAG. NO:1099) (SEQ. ID NO:1 108) (FRAG. NO:1100) (SEQ. ID NO:1109) (FRAG. NO:I 101) (SEQ. ID NO:1 110) (FRAG. NO:1102) (SEQ. ID NO:1111) 5'-UTCCTOOOCTOCOTOCOC (FRAG. NO: 1103) (SEQ. ID NO: 1112) (FRAG. NO:1104) (SEQ. ID NO:1113) :5-0GCB GOB OB BOO 0GB 000 COB TCB GOB 0GCB OCO TOB 0CC BBB GOB GOB CCB TG GOB BCO CBG CTC COO BBC 0GCB GOB 5'-CBG BOO TG C (FRAG. NO:1105) (SEQ. ID NO:2421) Human IL-4 Anti-sense Oligonucleotide Fragments 40 5'TCG T UO CT TGC UTC 0CC OOC BCB TG TBO GBG OBB OBB GBG BOG 000 BBO CBG UOG GOB GOT OBO BCC GBT TBB TBG OTOTCG B-3' (FRAG. NO: 1753) (SEQ. ID NO: 1766) BCB-3- (FRAG. NO: 1754) (SEQ. ID NO: 1767) 5'-T TGG UG-3- (FRAG. NO:1755) (SEQ. ID NO:1768) TOG UTG OCT TCC UTC-3' (FRAG. NO: 1106) (SEQ. ID NO: 1115) 5'-GCCGGCBCBTOCTBOCBGGBBGBBCBGBGGGGOOBBGBGTUGBGOTGBGBCCCBUrBBTBOGTGTCGB-3 (FRAG.NO:1107) (SEQ. ID NO:1116) Human 1L4 Receptor Anti-sense Oligonucleotide Fragment 0CC CG TCC 0CC GG TGT TCO OTO OCT COO CCC CG TGC UTG TCT TG CG 000 UTG OU CCT 000 CCT GOT TCT TG 000 COT U C GOT CTO CTO OCT GOT CTO GOC CG COG TG GG 000 TOG CUT OCT GUr CTG CCT 000 GTC TCC CCT CTC CTG CUUGTrCTCC CUGr CT CTG TCT TGC CTCG GT CT CTGOGT CCT CU GCCTO GOC OCT CUT CCC GTC 000 COO CTO COO GO CTC OTO CTO CCT GOT CG CTG GGT 000 GOT OCT CCT TCC CUT TCG CCO GTC OTO 000 TT OCO 000 CTO GG TG CCT 000 000 TCT 000 GCT T 000 OTG GOC TOG CTO CTG CUT COO 0CC 0CC TOO OCT TCC CTO TG CCC Trrr CCT CTG CTG GOT CCC CGT CCC OU- CCA AGG TG ACC OCA CG ACC OGC OCT ACA OGA CG AGC GAG OCA AGC ACC CAT 000 OAT CCA OOC CCA OCT OUT CGB BG TG BCC 0GCB CBO BCC GOC OCT BCB 0GB CBG BG CB 0GCB BG BCC GBT 000 GBT CGB GG CGB OCT 0 (FRAG. NO: 1756) (SEQ ID NO: 1769) 5'-TGTGCOC-3' (FRAG. NO: 1757) (SEQ ID NO: 1770) OCTGCT 0000 (FRAG. NO:1758) (SEQ. ID NO:1771) (FRAG. NO: 1108) (SEQ. ID NO: 1117) H:\Gabriela\Keep\Speci\93951 -98doc 05/07/02 (FRAG. NO:1 109) (SEQ. ID NO: 1118) 5'-CGTGTGGGCF1CGG (FRAG. NO: I I10) (SEQ. ID NO: 1119) (FRAG. NO: I I11) (SEQ. ID NO: 1120) (FRAG. NO:1112) (SEQ. ID NO:1121) 5'-GTTCCTGOGGCCCTG'FrrC (FRAG. NO:1113) (SEQ. ID NO:1122) (FRAG. NO:1114) (SEQ. ID NO:1123) (FRAG. NO:1I115) (SEQ. ID NOA1124) (FRAG. NOA 116) (SEQ. ID NO: 1125) (FRAG. NO:1 1117) (SEQ. ID NO: 1126) 5'-C'F1GGCTGGTTCCTGGCCTCGGG (FRAG. NO:1118) (SEQ. ID NO:1127) 5'-CCTCCTCCTCCTCCTCGCTCCCTF17CT1CCTCT (FRAG. NO:1119) (SEQ. ID NO: 1128) (FRAG. NO: 1120) (SEQ. ID NO: 1129) (FRAG. NO:1121) (SEQ. ID NO:1130) (FRAG. NO:1122) (SEQ. ID NO:1131) 5'-GGCTGCTCC'ITGCCCC (FRAG. NO: 1123) (SEQ. ID NO: 1132) (FRAG. NO:1 124) (SEQ. ID NO:1133) (FRAG. NO:1125) (SEQ. ID NO:1134) (FRAG. NO:1126) (SEQ. ID NO:l 135) (FRAG. NO:1 127) (SEQ. ID NO: 1136) 5'-CCrTrCCCCCOGCTCC (FRAG. NO:1128) (SEQ. ID NO:1137) (FRAG. NO: 1129) (SEQ. ID NO: 1138) GGT CTG TGG CCT OCT CCT GGG G (FRAG. NO:1130) (SEQ. ID NO:1139) 5-AGGGGTCTGGGOCCC1C (FRAG. NO:1131) (SEQ. ID NO:1140) 5'-FFFTGGGGTCTGGCF1G (FRAG. NO:1132) (SEQ. ID NO:1141) 5'-GCCTGGCTGCCTFCC (FRAG. NO:1133) (SEQ. ID NO:1142) (FRAG. NO:1134) (SEQ. ID NO:1143) 5'-TGTCCTCTGTOFCTCCCCF1 (FRAG. NO:1135) (SEQ. ID NO:1144) (FRAG. NO:1136) (SEQ. ID NO:1145) 5-GGTT1CCCGCCF1CCCT (FRAG. NO: 1137) (SEQ. ID NO:1146) 5'-'F17 CCC AGA GCT TGC CAC CTG CAG CAG GAG CAG GCA GCT CAC AGG GAA GAG GAG CCC AGA GCA AAG CCA CCC CAT TGG GAG ATG CCA AGG CAG GAG GCT G (FRAG. NO:1138) (SEQ. ID NO:1147) 5'-GF1 CCC BGB OCT TGC CBC CTG CBG CBG GBC CBG GCB GCT CBC BGG GBB CBG GBG CCC BOB 0GCB BBG CCB CCC CBT TGG GBG BTG CCB BGG CBC CBG GCT 0-3' (FRAG. NO:1139) (SEQ. ID NO:1148) Human IL5* Anti-sense Oligonucleotide Fragments 5'-TCCCTG'TfC CCCCCT-1TCG 'ITCTGCG'FIT GCC'TTTGGCG, T11T7O'T G'FTICTCTC TCCOTCTITC TITCTCCCCT GTGGGBB'17 CTGTGGGGBT GGCBTBCBCG TBGGCBGCTC CBBGBGCTBG CBBBCTCBBB TGCBGBBGCB TCCTCBTGGC TCTGBBBCGG TGOGAA'ITTC TGTGGGGBTG GCATACACGT AGGCAGCTCC AAGAGCTAGC AAACTCAAAT OCAGAAGCATC CTCATGGCTC TGAAACG-3' (FRAG. NO: 1759) (SEQ. ID NO: 1772) CCG GG-3' (FRAG. NO: 1760) (SEQ. ID NO: 1773) 5'-G GGTF1C T. (FRAG. NO: 1761) (SEQ. ID NO: 1774) :5'-GTG GO BTG GC-3' (FRAG. NO: 1762) (SEQ. ID NO:1775) *.5'-CCB BGB OCT BGC-3' (FRAG. NO: 1763) (SEQ. ID NO: 1776) CTG 'FIT CCC CCC 'I-3 (FRAG. NO:1140) (SEQ. ID NO:1 149) ~5'-CGT TCT GCO 'FF1 GCC 'FIT (JGC-3' (FRAG. NO:1141)(SEQ. ID NO:l 150) 5'-OTT 'FF1 TGT TFIG 'TI7 TCT-3' (FRAG. NO:1142)(SEQ. ID NO:1151 TCC GTC 'FF1 CTF1 CTC C-3 (FRAG. NOA1143) (SEQ. ID NO:1152) CCT GCC TGT GTC CCT GCT CCC C-3- (FRAG. NO:1144) (SEQ. ID NO:1153) GGT 'F1C TGG CTT CCT CTC T-3' (FRAG. NO:1 145) (SEQ. ID NO:1154) 5'-TGT CTC TCT GTC CIT 'ITG, 1T.3'(FRAG. NO: 1146) (SEQ. ID NO:1155) 50 5'-TOT TOT GCG 0CC TGG TGC TOC CCT GCC CCG GG-3' (FRAG. NO: 1147) (SEQ. ID NO:1156) OGA ATT TCT OTG GOG BTO OCA TAC ACO TAG GCA OCT CCA AGA OCT AGC AAA CTC AAA TOC AGA AOC ATC CTC ATG OCT CTO AAA CG-3 (FRAG. NO: 1764) (SEQ. ID NO: 1777) 0GB B'IT TCT OTG 000 BTG GCB TBC BCO TBO GCB GCT CCB BOB OCT BGC BBB CTC BBB TOC BOB BOC BTC CTC BTO OCT CTG BBB CO-3' (FRAG. NOA 148) (SEQ. ID NOA1157) Human IL-5 Receptor Anti-sense Oligonucleotide Fragments TGAGTAATAC ATGCGCCACG ATGATCATAT CCFF=ACT ATGAGGCCGT OTOTC'FITOC TGTOCCCTGC CTCTCTOCC COTOTCTOTC OTGTCT1TGC 'FITGCTC'FI' OTOTOTC'FIT OCTGTGCCCT OCCTCTCTOC-3' (FRAG. NO: 1765) (SEQ. ID NO: 1778) 5'-CG TOT C-3- (FRAG. NO: 1766) (SEQ. ID NO: 1779) H:\Gabricla\Keep\Speci\939S1 '98.doc 05/07/02 5'-GCCCTGCC-3- (FRAG. NO: 1767) (SEQ. ID NO: 1780) TOTCTG TCG TGTCT-3' (FRAG. NO:1149) (SEQ. ID NO:2423) 5'-TfCC1TfGCTCT-rG-3' (FRAG. NO:1150) (SEQ. ID NO:1159) 5'-GTGTGTCTITGCTGT-3' (FRAG. NO:1151) (SEQ. ID NO:1158) 5'-GCCCTGCCTCTCTGC-3' (FRAG. NO:1152) (SEQ. ID NO:1161) CBGTGGCCCC CBBBBGGBTG BGTBBTBCBT GCGCCBCGBT GBTCBTBTCC 1T1TMBCTBT GBGG-3' (FRAG.NO:1768) (SEQ. ID NO: 1781) Human IL-6 Receptor Fragments TCCTGCCGCG TCTCTGGGCC GTCCCGTCCC TCGGCCCCGC GCCGCGCTCG GCTCCTCTCC CTCTGGCCCG GCTCGGGGCG GGGCGGGGCG GTGGGCGGGC GGCGCTGCCC TGCGCGCGGC GCTGGCCCCT GCTGGCCGTC GGCTGCGCGC TGCTGGCTGC CCTGCTGGCC GCGCCGGGGC CTGTCCGCCT CTGCGGGCGC TGTCTCCTGG CTrGTC'rrCC GGCTCT7CTG CTGGGGTGGG GCTGGGCGGC CGGCCCGGTG CTOGGGCTCC TCGGGGGGGO GGGCTCT7CC GGGCTGTCTC CCTCCGGGGC GGGGG1TCT GGCCGTGGGG GTCTTGCCTG GCCTCCGGGC TCCTGCTrGT CT-rGCCTTCC UTCTCTGGTC GGT-rGTGGCT CGGGGCTCCG TGGGTCCCTG GCGCCCGTTr GTGTI-FGTC YTTCCCCTG GCGTCCCTGT GCCCCTCTCC TCTCC'TrCCT CTGCTTCTCG CTCTCCY=G TGGGGCCCTC CCTGCTGCTC T7GGTMGG GCTTMC TC17CCTCCT TITCGTGCG TGGGCCTCCG CACGCCTCT17 GCCACCTCCT GCGCAGGGCA GCGCCTTGG GGCCAGCGCC GCTCCCGGCG CGGCCAGCAG GGCAGCCAGC AGCGCGCAGC CGACGOCCAG CATGCTTCCT CCTCGGCTAC CACTCCATGG TCCCGCAGAG GCGGACAGGC GCBCGCCTC UTGCCBCCTC CTGCGCBGGG CBGCGCCTTG GGGCCBGCGC CGCTCCCGGC GCGGCCBGCB GGGCBGCCBG CBGCGCGCBG CCGBCGGCCB GCBTGCTJ7CC TCCTCGGCTB CCBCTCCBTG GTCCCGCBGB GGCGGBCBGG C-3' (FRAG. NO: 1769) (SEQ.

ID NO: 1782) 5'-CCCGGCGC-3- (FRAG. NO:1184) (SEQ. ID NO:1193) 5'-OGCCBGCBGG-3' (FRAG. NO:1186) (SEQ. ID NO:1195) 5'-GCBGCCBGCBGCG-3' (FRAG. NO: 1770) (SEQ. ID NO: 1783) 5'-C GCBGCCGBCGGCC (FRAG. NO: 1771) (SEQ. ID NO: 1784) 5'-GGGGGTGGCTCCTGCC3'- (FRAG. NO:1 153) (SEQ. ID NO:1 162) 5*-GCGTCTCTGGGCCGTCCC-3' (FRAG. NO:1 154) (SEQ. ID NO:1163) 5'-GTCCCTCGGCCCCGCGCCGCGCTCGGCTCCTCTCCC-3- (FRAG. NO:1 155) (SEQ. ID NO:1 164) 5'-TCTGGCCCGGCTC-3' (FRAG. NO:1 156) (SEQ. ID NO:1 165) 5'-OGGGCGGGGCGGGGCGGTGGGCGGGC-3' (FRAG. NO:1 157) (SEQ. ID NO:1 166) 5'-GGCGCTGCCCTGCGC-3' (FRAG. NO:1158) (SEQ. ID NO:1167) 5'-GCGGCGCTGGCCCC-3' (FRAG. NO:1159) (SEQ. ID NO:2424) 5'-TGCTGGCCGTCGGCTGCGCGCTGCTGGCTGCCCT-3' (FRAG. NO:1 160) (SEQ. ID NO:1 168) 5'-GCTGGCCGCGCCGGG-3' (FRAG. NO:1161) (SEQ. ID NO:1170) 5'-GCCTGTCCGCCTCTGCGGG-3' (FRAG. NO:1162) (SEQ. ID NO:1171) 5'-CGCTGTCTCCTGGC-3- (FRAG. NO:1163) (SEQ. ID NO:1172) 5'-TfGTCTrCCGGCTCT-3' (FRAG. NO:1164) (SEQ. ID NO:1173) 5'-TCTGCTGGGGTGGG-3' (FRAG. NO:1165) (SEQ. ID NO:1174) 40 5'-GCTGGGCGGCCGGCCCGGT-3- (FRAG. NO:1166) (SEQ. ID NO:1175) 5'-GCTGGGGCTCCTCGGGGGG-3' (FRAG. NO:1167) (SEQ. ID NO:1176) 5'-GGGGGCTCT7CCGG-3' (FRAC. NO:1168) (SEQ. ID NO:1177) 5'-GCTGTCTCCCTCCGGG-3' (FRAG. NO:1169) (SEQ. ID NO:1178) 5'-GCGGGGGTI'CTGGCC-3' (FRAG. NO:1170) (SEQ. ID NO:1179) 5'-GTGGGGGTCTrGCC-3' (FRAG. NO:1171) (SEQ. ID NO:1180) 45: 5'-TGGCCTCCGGGCTCC-3' (FRAG. NO:1172) (SEQ. ID NO:1 181) ~5'-TGCTTGTCTTGCCTITCCTTC-3' (FRAG. NO:1173) (SEQ. ID NO:I182) 5Y-TCTGGTCGGTTGTGGCTCG-3' (FRAG. NO:1174) (SEQ. ID NO:1183) 5'-GGGCTCCGTGGGTCCCTGGC-3- (FRAG. NO:1175) (SEQ. ID NO:1184) 5'-GCCCGTIGTGITIGTC-3' (FRAG. NO:1176) (SEQ. ID NO:1185) 5'-3TICCCCTGGCGT-3' (FRAG. NO:1177) (SEQ. ID NO:1186) 5'-CCCTGTGCCCCTCTCCTCTCCT-rCCTCTGCTrCTC-3' (FRAG. NO:1178) (SEQ. ID NO:1I87) 5'-GCTCTCCTTrGTGGG-3' (FRAG. NO:1179) (SEQ. ID NO:1188) 5'-GCCCTCCCTGCTGCT-3' (FRAG. NO:1180) (SEQ. ID NO:1189) 5-CkrGG1TI17GGGCT-3' (FRAG. NO:1181) (SEQ. ID NO:1190) 5'-ITfTTCTCTTCCTCCTITTC-3' (FRAG. NO:1182) (SEQ. ID NO:1191 5'-GTGCGTGGGCCTCC-3' (FRAG. NO:1183) (SEQ. ID NO:1192) TGCCACCTCC TGCGCAGGGC AGCGCCTrGG GGCCAGCGCC GCTCCCGGCG CGGCCAGCAG GGCAGCCAGC AGCGCGCAGC CGACGGCCAG CATGCTTCCT CCTCGGCTAC CACTCCATGG TCCCGCAGAG 60 5'-GCBCGCCTGTr GCCBCCTCCT GCGCBGGGCB GCGCCTTGGG GCCBGCGCCG CTCCCGGCGC GGCCBGCBGG GCBGCCBGCB GCGCGCBGCC GBCGGCCBGC BTGCTTCCTC CTCGGCTBCC BCTCCBTGGT CCCGCBGBGG CGGBCBGGC-3' H:\rea\Kep\Spci9395 -98.dov 05/07/02 (FRAG. NO: 1187) (SEQ. ID NO: 1196) Human IL-6 Anti-sense Oligonucleotide Fragments TCCTGCCGCG TCTCTGGGCC GTCCCGTCCC TCGGCCCCGC GCCGCGCTCG OCTCCTCTCC CTCTGGCCCO GCTCGGOGCO GOGGGGO OTGOCGOC GGCGCTGCCC TGCGCGCGGC GCTGGCCCCT GCTGGCCGTC OGCTGCGCGC TGCTGGCTGC CCTGCTGGCC GCGCCGGGGC CTGTCCGCCT CTGCGGGCGC TGTCTCCTGG C1TGTCT-rCC GGCTCTrCTG CTGGGGTGOG GCTGGGCGGC CGGCCCGGTG CTGGGGCTCC TCGGGGGGGG GGGCTCTTCC GGGCTGTCTC CCTCCGGGGC GGGGGMTCT GGCCGTGGGG GTCTTGCCTO GCCTCCGGGC TCCTGCT-rGT CTTGCCYI7CC TTCTCTGGTC GGT7GTGGCT CGGGGCTCCG TGOGTCCCTG GCGCCCG'IT GTGTITFGTC TITT1CCCCTG GCGTCCCTGT GCCCCTCTCC TCTCCT-rCCT CTOC1TCTCG CTCTCCTG TGGGGCCCTC CCTOCTGCTC TTGGTM~GG GCTI7TITC TCT17CCTCCT 1TFCGTGCG TGGGCCTCC GCACGCCTCT TGCCACCTCC TOCGCAGGGC AGCGCCU7GG GOCCAGCGCC GCTCCCGGCG CGGCCAGCAG GGCAGCCAGC AGCOCGCAGC CGACGGCCAG CATGCT7CCT CCTCGGCTAC CACTCCATGG TCCCGCAOAG GCGGACAGGC GCBCGCCTC YrOCCBCCTC CTGCGCBGGG CBGCGCC1TG GGGCCBGCGC CGCTCCCGOC GCGGCCBGCB GGGCBGCCBG CBOCGCGCBG CCGBCGGCCB GCBTGCYrCC TCCTCGOCTB CCBCTCCBTO GTCCCGCBGB GGCGGBCBGG C-3' (FRAC. NO:1772) (SEQ.

ID NO:1782) 5'-GGGGCBGG-3' (FRAG. NO:1773) (SEQ. ID NO:1786) CBGOC-3' (FRAG. NO:1774) (SEQ. ID NO:1787) CCCC-3' (FRAG. NO:1775) (SEQ. ID NO:1788) BGBBGGCBBC-3' (FRAG. NO:1776) (SEQ. ID NO:1789) 5'-GCT TCT CU TCGT-rC CCG OTG GGC TCG-3- (FRAG. NO:1188) (SEQ. ID NO:1197) GCT GTC TGT OTOGGCOOCT-3- (FRAG. NO:1189) (SEQ. ID NO:1198) CCT CiTTGC TGC TlT C-3' (FRAG. NO:1190) (SEQ. ID NO:1199) TCTTUG CCT TIT TCT OC-3' (FRAG. NO:1191) (SEQ. ID NO:1200) TBCTGGOGCB GGGBBGGCBG CBGGCBBCBC CBGGBGCBGC CCCBOGGBGB BGGCBBCTG BCCGBBGGCG CT-rGTGGBGB BGGBGUrCBT BGCTGGGCTC CTGGBGGGGB GBTBGBGC-3(FRAG.NO: 777) (SEQ.ID NO: 1790) Human Monocyte-derived Neutrophil Chemotactic Factor Anti-sense Oligonucleotide Fragments GGITTGBGT BTGTCTTTBT GCBCTGBCBT CTBBGTTU TBGCBCTCCT TGGCBBBBCT GCBCCTTCBC BCBGBGCTGC BGBBBTCBGG BBGGCTGCCB BGBGBGCCBC GGCCBGCTTG GBBGTCBTGT TTBCBCBCBG TGBGBTGGTr CCTTCCGGGC U-GTGTGCTC TGCTGTCTCT TGGTCCUrC CGGTGGTITC TFCCTGGCTC TTGTCCT1TC TCUrGG CCCT TGGC-3' (FRAG. NO: 1778) (SEQ. ID NO: 1791) BTG-3' (FRAG. NO:1779) (SEQ. ID NO: 1792) CT-3' (FRAG. NO:1780) (SEQ. ID NO:1793) GTG G-3' (FRAG. NO:1781) (SEQ. ID NO: 1794) 5'-OG CCC iTO GC-3' (FRAG. NO:1782) (SEQ. ID NO: 1795) 5'-OCT TGT GTG CTC TG TGT CTC T-3' (FRAG. NO:1 192) (SEQ. ID NO:1201) TIC CUCCG GTG GU TCT TCC TGCTCiTO TCC T-3' (FRAG. NO:1193) (SEQ. ID NO:1202) Y-iTCTCTTGGCCCiTGGC-3Y(FRAG.NO:1194)(SEQ.IDNO:203) CBG~T BCCCTTOBBC 40 GCBCCTJTCBC BCBGBOC-3' (FRAG. NO:1783) (SEQ. ID NO: 1796) Human Neutrophil Elastase (Medullasin) Anti-sense Oligonucleotide Fraliments CGCGBGBGOT TBTGOGCTCC CBGGBCCBCC CGCBCCGCGC GGBCGTBC B1TCGCCBCG CBGTGCGCGG CCOBCBTGBC GBBGiTOGOC GCBBTCBGGG TGGCGCCGCB GBBGTGGCCT CCGCGCBGCT GCBOGGBCBC CBTGBBGGGC CBCGCGTGOG GCCOCOCTCG CCOOCCCCCC BCBBTCTCCG BGGCCBGCGC GGTGCCCCCC BOCBGCBBGG CCGGCBGOBC BCBGGCOBGG BGBCBCGCGB GTCGGCOGCC GBGOTCBTG GTGGGGCTGO GGCTCCGOOG TCTCTGCCCC TCCGTGCTGG TGGGGCTGGG GCTCCGGGG TCTCTGCCCC TCCGTOCCOC GTGGGGCCGC GCTCGCCGGC CCCCCCCTOC CGGGTGGGCT CCCGCCGCGC GCCGGCCTGC CGGCCCCTCG TGGGTCCTGC TGGCCGGGTC CGGGTCCCGG GGGTOOGGCG COBOTCGGCG GCCGBGGGTC-3' (FRAG. NO:1784) (SEQ. ID NO: 1797) 5'-GG TOG GGC-3' (FRAG. NO:1785) (SEQ. ID NO: 1833) 000 CCO JY (FRAG. NO:1786) (SEQ. ID NO:1799) GGC CGG GTC CGG G-3' (FRAG. NO: 1787) (SEQ. ID NO: 1800) TGG OGC TCC GGGTC TCT GCC CCT CCG TGC-3' (FRAG. NO:1 195) (SEQ. ID NO:1204) GTG GGG CCG CGC TCG CCG GCC CCC C-3' (FRAG. NO:1I96) (SEQ. ID NO:1205) 555-CCT GCC GGTGG OCT CCC GCC GCG-3- (FRAG. NO:1197) (SEQ. ID NO:1206) CGG CCT 0CC GGC CCC TC-3' (FRAG. NO:1198) (SEQ. ID NO:1207) ~~5'-GTG GGT CCT GCT GGC CGG GTC CGG GTC CCG GGG GTG GGG-3- (FRAG. NO:1199) (SEQ. ID NO:1208) OBOTCOOCO 0CC OBO GTC-3' (FRAG. NO:1200) (SEQ. ID NO:1209) COCOBOBOOT TBTOOOCTCC CBOGBCCBCC COCBCCOCOC GGBCGTTTBC BTITCGCCBCG

CBGTGCOCOO

H:\Gabriela\Keep\Speci\939S1-98.doc 05/07/02 CCGBCBTGBC GBBGTrGGGC GCBBTCBGGG TGGCGCCGCB GBBGTGGCCT CCGCGCBGCT GCBGGGBCBC CBTOBBGGGC CBCGCGTGOG GCCGCGCTCG CCGGCCCCCC BCBBTCTCCG BGGCCBGCOC GGTGCCCCCC BGCBGCBBGG CCGGCBGGBC BCBGGCGBGG BGBCBCGCGB GTCGGCGGCC GBGGGTCBTG GTGGOGCTGG GGCTCCGGGG TCTCTGCCCC TCCGTOC-3- (FRAG. NO:1788) (SEQ. ID NO: 1801) Human Neutrophil Oxidase Factor Anti-sense Oligonucleotide Fragments GGTCCTGGBC GGCBCTGBBG GCBTCCBGGG CTCCCTrCCB GTCCTTC17G TCCGCTGCCB GCBCCCCUTC BU-CCBGBGG CTOBTGGCCT CCBCCBGGOB CBTOBTTBGG TBGBBBCTBG GBGGCCOOCC TCCBCCBGGO BCBTOGTCCT TCTTGTCCGC TGCCTCTCTG GGG1TICGG TCTGGOTGGG C1TTCCTCCT GGGGCTGCTG CTGGGCTCTT CT-TYGTI-T CTGOCCTOOT GCTCTCTCGT GCCC1TrCCC UTGOOTGTCT TG1TTMIGTG GCCTCCBCCB GGGBCBTG-3' (FRAG. NO:1789) (SEQ. ID NO: 1802) 00-3 '(FRAG.NO: 1790) (SEQ. ID NO: 1803) 5'-GCCBGCBCCCC-3' (FRAG.NO:1791) (SEQ. ID NO: 1804) CBC CBG-3' (FRAG.NO: 1792) (SEQ. ID NO: 1805) CTC CBC CBG GGB CBT G-3'(FRAG. NO:1201) (SEQ. ID NO:1210) 5'-GTC CUT CUT GTC CGC TG C -3'(FRAG. NO:1202) (SEQ. ID NO:121 1) CTG GGG rrr TCG OTC TGG OTG G-3 (FRAG. NO:1203) (SEQ. ID NO:1212) UTC CTC CTG GGO CTG CTG CTG-3' (FRAG. NO:1204) (SEQ. ID NO:1213) TCT TCTT rr TT UC TGG CCT GOTG-3- (FRAG. NO:1205) (SEQ. ID NO:1214) TCT COTGCC CU TCC-3' (FRAG. NO:1206) (SEQ. ID NO:1215) 5'-CUGGTGT CU GU YIf GT-3' (FRAG. NO:1207) (SEQ. ID NO:12 16) CTC CBC CBG GGB CBT G-3- (FRAG. NO:1208) (SEQ. ID NO:1210) GGTCCTGGBC GGCBCTGBBG GCBTCCBGGG CTCCCTTCCB GTCCU-CUTG TCCGCTGCCB GCBCCCCUrC BUFCCBGBGG CTGBTGGCCT CCBCCBGGOB CBTOBU-BGG TBGBBBCTBO GBGGCC- 3'(FRAG.NO:1793)(SEQ.ID NO:1806) Human Cathepsin G Anti-sense Oligonucleotide Fragments CTGCTCTGBC CTOCTGOBCT CTOGBTCTGB BOBTBCGCCB TOTBOGGOCO GOBOTOGOGC CTOCTCTCCC GGCCTCCGBT GBTCTCCCCT GCCTCBGCCC CBGTGGGTBO OBGBBBGGCC BOCBOBBOCB GOBOTOOCTO CBTCYTI7CCT GOTOGGGCCT GCTCTCCCGG CCTCCGTOTG UOGCTOOGTG TITCCCGTC TCTGGTCTGC CTCOGGOOGT COT-3- (FRAG. NO:1794) (SEQ. ID NO: 1807) 5'-GBBOBTBCOCC-3' (FRAG. NO:1795) (SEQ. ID NO: 1808) 5'-CBOCCCCBG-3' (FRAG. NO: 1796) (SEQ. ID NO: 1809) COT CTC TGG-3' (FRAG. NO:1797) (SEQ. ID NO:18 5'-GTGG000CCT OCT CTC CCG 0CC TCC 0-3' (FRAG. NO:1209) (SEQ. ID NO:1218) OUT OCT GO OTO rr-r TCC COT CTC TGO-3' (FRAG. NO:1210) (SEQ. ID NO:1219) 5'-TCT GCC UTC 000 GOT COT-3' (FRAG. NO:1211) (SEQ. ID NO:1220) 5'-CCCTCCBCBT CTOCTCTOBC CTGCTOGBCT CTGGBTCTOB BGBTBCOCCB TOTBGOOCO GGBGTGOGC CTOCTCTCCC GGCCTCCGBT GBTCTCCCCT GCCTCBGCCC CBGTGGGTBO GBGBBBGOCC BGCBGBBGCII OBGTOOCTO-3' (FRAG. NO: 1798) (SEQ. ID NO: 1811) Human Defensin 1 Anti-sense Oliaonucleotide Fragments 40 5-CCOGGGCTGC BGCBBCCTCB TCBOCTCUOG CCTGGBGTGO CTCBOCCTGO OCCTOCBGGG CCBCCBGGBO BBTGGCBGCB BOOBTOOCGB GGGTCCTCBT GGCTGGGGTC BCBGBTCCTC TBGCTBGGCB GGOTOBCCBO BOBGGGC 000 TCC TCB TOG CTG GOG GCC TOG 0CC TG BGG GCC OCT CUT 0CC TOG BOT GOC TC 0CC CBO BGT CUT CCC TOG T-3' (FRAG.NO:1 799) (SEQ. ID NO: 1812) 5'-CCOOGGC-3'(FRAG.NO:1800) (SEQ. ID NO: 1813) 5'-GO OCCTOCBGGO CC-3' (FRAG.NO:1801) (SEQ. ID NO: 1814) BOO-3 (FRAG.NO:I802) (SEQ. ID NO: 1815) :5-G TCC TCB TOG CTG G00-3' (FRAG. NO:1212) (SEQ. ID NO:1221) TG GCCTGCBGGGCC-'(FAG. O:113)(SEQ. ID NO:1222) 5'-OCT CUT GCC TGG BOT GGC TC-3' (FRAG. NO:1214) (SEQ. ID NO:1223) 5'-6CC CBO BOT CUr CCC TOG T-3 (FRAG. NO:1215) (SEQ. ID NO:1224) BOCBBCCTCB TCBOCTCU-G CCTOOBOTOG CTCBOCCTGO GCCTOCBOGG CCBCCBGGBG BBTGOCBOCB BOOBTOOCOB GOTCCTCBT GOCTGGGGTC BCBOBTCCTC TBGCTBOGCB GOGTOBCCBO BGBGGGC-31 (FRAG.NO:1803) (SEQ. ID NO: 1816) Human Defensin 3 Anti-sense Oligonucleotide Fra2ments H:\GaieaKepSpeci'93951I-98.doc 05/07/02 TGCTCCGGGG CTGCBGCBBC CTCBTCBGCTC TTGCCTGGBGTG GCTCBGCCTGG GCCTGCBGGG CCBCCBGGBGB BTGGCBGCBBG GBTGGCGBGGG TCCTCBTGGC TGGGGTCBCCT GGBGGBGGGB GBGCBGGGGG TCCTCBTGGC TGGGGTCCCT CTCTCCCGTC CT-3- (FRAG. NO:1804) (SEQ. ID NO:1817) 5'-GGCBGCBBGG-3- (FRAG. NO:1805) (SEQ. ID NO:1818) 5'-GG CTG GGG-3' (FRAG. NO:1806) (SEQ. ID NO:1819) 5'-GGGGTCBCC-3- (FRAG. NO:1807) (SEQ. ID NO:1820) TCC TCB TGG CTG GGG TC-3' (FRAG. NO:1216) (SEQ. ID NO:1225) CTC TCC CGT CCT-3' (FRAG. NO:1217) (SEQ. ID NO:1226) TGCTCCGGGG CTGCBGCBBC CTCBTCBGCTC TTGCCTGGBGTG GCTCBGCCTGG GCCTGCBGGG CCBCCBGGBGB BTGGCBGCBBG GBTGGCGBGGG TCCTCBTGGC TGGGGTCBCCT GGBGGBGGGB GBGCBGG-31 (FRAG. NO:1808) (SEQ. ID NO:1821) Human Macrophage Inflammatory Protein-1-alphaIRANTES Receptor Anti-sense Olillonucleotide Fragments 5'-GTCTrGTY1r CTGGGCTCGT GCCCCBTCCC GGCYI7CTCTC TGGITCCGTC CTCTGTGGTG 1TGGCCCTG CTTCC1TMG CCTGTTGAGG GGGCAGCAGT TGGGCCCCAA AGGCCCTCTC GTTCACCTrFC TGGCACGGAGTT GCATCCCCATA GTCAAACTCT GTGOTCGTGT CATAGTCCTC TGTGGTGTITr GGAG7TTCCA TCCCGGCTrC TCTCTGGYITC CAAGGGAGB GGGGGCBGCB GTrGGGCCCC BBBGGCCCTC TCGTTFCBCCT TCTGGCBCGG BGITrGCBTCC CCBTBGTCBB BCTCTGTGGT CGTGTCBTBG TCCTCTGTGG TGTTTGGBGT T-rCCBTCCCG GCYI'CTCTCT GGTITCCBBGG GB-3'(FRAG.NO:1809)(SEQ.ID NO:1822) 5-GGGCC CC-3' (FRAG. NO:1810) (SEQ. ID NO:1823) 5'-GGGGGCBGC-3- (FRAG. NO:1811) (SEQ. ID NO:1824) 5'-CCCGGCTJTC-3- (FRAG. NO:1812) (SEQ. ID NO:1825) YTf G'IT TCT GGG CTC GTG CC-3' (FRAG. NO:1218) (SEQ. ID NO:1227) TCC CGG CTF CTC TCT GGTTCC-3- (FRAG. NO:1219) (SEQ. ID NO:1228) 5'-GTC CTCTGT GGT GU TGG-3' (FRAG. NO:1220) (SEQ. ID NO:I229) TGC rC er TfGCCT GTh3' (FRAG. NO:1221) (SEQ. ID NO:1230) S'-GAGGGGGCAGC AGTrGGGCCC CAAAGGCCCT CTCGTTCACC TTCTGGCACG GAG'ITGCATC CCCATAGTCA AACTCTGTGG TCGT-3' (FRAG. NO:1222) (SEQ. ID NO:1231) 5'-GTCATAGTCCTCTGTGGTGTTGGAGTrCCATCCCGGCTTCTCTCTGG1TCCAAGGGA-3' (FRAG. NO:1223) (SEQ. ID NO: 1232) 5'-GBGGGGGCBG CBGTTGGGCC CCBBBGGCCC TCTCG17CBC CTTCTGGCBC GGBGTTGCBT CCCCBTBGTC BBBCTCTGTG GTCGTG-3' (FRAG. NO:1224) (SEQ. ID NO:1233) 5Y-TCBTBGTCCTCTGTGGTG~rrGGBGTICCBTCCCGGCTTCTCTCTGGTTCCBBGGGB-3' (FRAG. .NO: 1225) (SEQ. ID NO:1234) RANTES Antisense Oligonucleotide Fragments CBGTGGGCGG GCBBTGTBGG CBBBGCBGCB GGGTGTGGTG TCCGBGGBBT BTGGGGBGGC BGBTGCBGGB GCGCBGBGGG CBGTBGCBBT GBGGBTGBCB GCGBGGCGTG CCGCGGBGBC CYITCBTGGTB CCTGTGGBGB GGCTGTCGGB GGGGGTGTGG TGTCCGCTTG GCGGTTCT7 CGGGTGITC TTCTCTGGGT TGGCCTGCTG CTCGTCGTGGT CGCTCCGCTC CCGGG'I17CGT CTCGCTCTGT CGCCCCITCC TrCCTGTCG TGTTCCTCCC TTCM1GCCT :CT-3' (FRAG. NO: 1813) (SEQ. In NO: 1826) 0 5'-GGTFGGC-3- (FRAG. NO: 1814) (SEQ. ID NO: 1827) 5'-CGGGG CBG-3' (FRAG. NO: 1815) (SEQ. In NO: 1828) 5'-CCCGGGTTCG-3' (FRAG. NO: 1816) (SEQ. ID NO: 1829) 5'-GGGTGTGGTG-3' (FRAG. NO: 1817) (SEQ. ID NO: 1830) CBGTGGGCGG GCBBTGTBGG CBBBGCBGCB GGGTGTGGTG TCCGBGGBBT BTGGGGBGGC BGBTGCBGGB GCGC-3' (FRAG. NO:1226) (SEQ. ID NO:1235) 45 5'-BGBGGGCBGT BGCBBTGBGG BTGBCBGCGB GGCGTGCCGC GGBGBCCT-rC BTGGTBCCTG TGGBGBGGCT GTCGGBGG-3' (FRAG. NO:1227) (SEQ. In NO:1236) 5S-GGTGTGGTGTCCGCTrGGCGGTrFCTrrCGGGTGMrCTCTCTGGGT'GGCCTGCTGCTCGTCGTGGTC-3

(FRAG.

NO:1228) (SEQ. ID NO:1237) 5'-GCTCCGCTCCCGGGTrCGTCTCGCTCTGTCGCCCCTrCC'I1CCTrGTCGTGTrCCTCCCT-rCCTrGCCTCT-3'(FRAG.

50 NO:1229) (SEQ. ID NO:1238) 5'-GGGTGTGGTGTCCG-3' (FRAG. NO:1230) (SEQ. In NO:1239) 5'-CTflTGGCGGTTFCTFCGGGTG-3' (FRAG. NO:1231) (SEQ. ID NO:1240) 5'-1TrCT-rCTCTGGG~rGGC-3' (FRAG. NO:1232) (SEQ. ID NO:1241) 0 5'-CTGCTGCTCGTCGTGGTC-3' (FRAG. NO:1233) (SEQ. ID NO:1242) *0.

J0 z H:NGabiela\Keep\Spc/93951I-98.doc 05/07/02 54 5'4GCTCGCTCCCGGGT7C-3' (FRAG. NO:1234) (SEQ. ID NO:1243) 5'-GTCTGTCTrGTCGCCC-3' (FRAG. NO:1235) (SEQ. ID NO:1244) 5'-CTUGTCCTUGTC-3- (FRAG. NO:1236) (SEQ. ID NO:1245) 5'-GTGTUCCTCCCTTCCYUGCCTCT-3' (FRAG. NO:1237) (SEQ. ID NO:1246) 5'-GGGCBGGGG CBGTGGGCGG GCBBTOTBGG CBBBGCBGCB GGGTGTOGTG TCGGBGGBBT BTGGGGBGGC BGBTGCBOGB GCGCBGBGOG CBGTBGCBBT OBGOBTGBCB GCGBGGCGTG CCGCGGBGBC GT-UCBTGGTB CCTGTGOBGB GGCTGTCGGB 00.3' (FRAG. NO:1818) (SEQ. ID NO:1831) Human Muscarinic Acetylcholine Receptor HM1* Anti-sense Oligonucleotide Fragments GGGGTGTGCG CTTGGCGCTC CCGTGCTCGG TTGTCTGTCT CCCGGTCCCG GTTGCCTGGC GTCTCGGGCC TTCGTCCTCT TCCTCT-FCTT CCTI7CCGCTC CGTGGGGGCT GCTITGGTGGG GGCCTGTGCCT CGGGGTCCCG GGGCTTCTGG CCCTUGCCGT TCATGGTGGC TAGGTGGGGC 0'ITC!BTGGTG GCTBGGTGGG GC-3' (FRAG.

NO: 1819) (SEQ. ID NO: 1832) 5'.4JGTGGGGC-3 (FRAG. NO:1820) (SEQ. ID NO: 1833) 5'-OCCCGGCGGGG-3 (FRAG. NO:1821) (SEQ. ID NO: 1834) 5'-CGG GOC TUG TGG CCC-3' (FRAG. NO:1822) (SEQ. ID NO: 1835) CBT GGT GGC TBG GTG GGG C-3- (FRAG. NO: 1238) (SEQ. ID NO: 1247) GCC CGG CGG GGT GTG CGC TUG GC-3' (FRAG. NO:1239) (SEQ. ID NO:1248) CCC GTG CTC GGT TCT CTG TCT CCC GGT-3' (FRAG. NO:1240) (SEQ. ID NO:1249) CCT TUG CCT GGC GTC TCG G-3' (FRAG. NO:1241) (SEQ. ID NO:1250) 5'-0CC TTC GTC CTC TUGC CTC -17C TUC CTU CC-3' (FRAG. NO:1242) (SEQ. ID NO:1251) CCG TGG GGG CTG CTU GGT GGG GOCCTG TGC CTC GGG GTC C-3' (FRAG. NO:1243) (SEQ. ID NO:1252) GGC TUG TGG CCC TUG CC-3' (FRAG. NO: 1244) (SEQ. I D NO: 1253) CAT GOT GGC TAG GTG GOG C-3- (FRAG. NO: 1245) (SEQ. I D NO: 1254) Human Muscarinic Acetylcholine Receptor HM3* Anti-sense Oligonucleotide Fragments 5'-OGG GTG GGT BGG CCG TOT CTG GGGGTU GGC CBT GTT GGT TGC CTCT TGG TGG TGC GCC GOG CGCG TCT TG CTUr TCT TCT CCT TCG GGC CCT CGG GCC GOT GCT TOT GGGCT CCT CCC GGG CGG CCT CCC CGG GCG GGG GCT TCT TGGCG CTG GCG GGG GGG CCT CCTGCT CTG TGG CT0 GGC GTU CCT TGG TOT TCT GGG TGGTGG COG GCG TG TG CCT CTG TGGGGG CCC GCG GCT GCB GGG GU7G CCT GTC TGC TTC GTCCTT TGC GCT CCC GGG CCG CCGGO GTG GGT AGO GCG TOT GTG GGGGTU OGC CAT GTT GOT TGC CGO CCC GO OCT GCA GOG G-31 (FRAG.NO:1823)(SEQ.ID NO:1836) 000 COG-3' (FRAG. NO:1824) (SEQ. ID NO:1837) OCO 000 000 CC-3' (FRAG. NO:1825) (SEQ. ID NO:1838) 000 CCO CC-3' (FRAG. NO: 1826) (SEQ. ID NO: 1839) CCO TGT-3' (FRAG. NO:1827) (SEQ. ID NO:1840) 5'-000 OTO GOT BOG CCG TOT CTG 000-3' (FRAG. NO:1246) (SEQ. ID NO:1255) GOC CBT OTT GOT TOC C-3' (FRAG. NO:1247) (SEQ. ID NO:1256) 5'-TCT TOG TOO TGCG0CC GGG C-3' (FRAG. NO:1248) (SEQ. ID NO:1257) TCT TOO CTU TGT TCT CGT TCG GG CCT COO 0CC GOT OCT TOT 00-3' (FRAG. NO: 1249) (SEQ. ID NO: 1258) CCT CCC 000 COO CCT CCC COG GO GGG OCT TGT TG-3' (FRAG. NO:1250) (SEQ. ID NO:1259) P. 40 5'-GCG CTO GCG 000 000 CCT CCT CC-3' (FRAG. NO: 1251) (SEQ. ID NO: 1260) CG TOO CTG GOC OTT CGT TOG TOT TCT 000 TOG C-3' (FRAG. NO:1252) (SEQ. ID NO:1261) COO OCO TOO TOO GCT CTO TOO TOG-3' (FRAG. NO:1253) (SEQ. ID NO:1262) eov. 5'-000 CCC GCG OCT 0GCB GOG 0-3- (FRAG. NO:1254) (SEQ. ID NO:1263) 5'-TTG CCT OTC TG TUG GTG-3' (FRAG. NO:1255) (SEQ. ID NO:1264) 5'-CTU TG OCT CCC GOG CG GG-3' (FRAG. NO:1256) (SEQ. ID NO:1265) OTO GOT AGO CCO TGT CTG 000-3' (FRAG. NO: 1257) (SEQ. ID NO: 1266) GOC CAT OTT GOT TG C-3' (FRAG. NO:1258) (SEQ. ID NO:1267) 5'-000 CCC OCO OCT OCA 000 0-3' (FRAG. NO:1259) (SEQ. ID NO:1268) Human Fibronectin* Antisense Oligonucleotide Fragments 5'-CG TTT CCT TUG COO TG TUG 0CC CG OCT CG GOT 0 CCC 0CC CG CCO CCO 0CC 0CC GC CCC 0CC 000 CTO 0 TCC CG CCC GC CCC GOC CCO 000 CG 000 00 COG CCC TCC CG CCC TCT 00 0CC GOC OCO GOC OTC GO GCG CTC OCO CCT 000 OTT CCC TGT CGT CCC CCT OTO C 0CC TG GTG TUFG CTG TUCTOC OTC CG TG GilT GTC CC CTC TCC TCO 0CC OTT 0CC TOT GC TOT CCG TCC TOT CG GCT TCC OTO OTO C TOT TOT CTG TUG TG CCT C 00 GOT OTO Cr0 OTO CTO OTO GTG OTO GGT Cr0 CCC OTO CrC OCCCTG, GCT 000 Cr0 0CC TGT TG GOT OTO OCT 55 TUG 000 CTC TCT TOO TUrG CCC I TU GTT CTC OTO OTO CGT CTG GTG GCT OOC TUG GTC OT TOT GTG 000 TOG, TG 00 TGC TCT CCC TTlT CCC TG TOO CG TTlT OT GGT OTU TUGC TOT CIT CGT CT TUG CrC Cr0 T-lT GTG COT TUG OCT 0. TG TG TUG CG GOC TOT GTG C CTU 0CC CCT OTO GG TU CCCTO TGG O OT CTU CTC CTU 000 GOT C 0CC CTUr GTU GOT 000 CTOGT COT CTO TGT TTr TGC TUG ~H:\Gabriela\Keep\Spcd\9395I -98doc 05/07/02 C TGG GGG TGG CCG T-G TGG GCG GTG TGG TCC GCC T TGC CTC TGC TGG TCT TrC-3' (FRAG. NO:.1828) (SEQ. ID NO: 1841) 5'-GGCCCGGGC-3- (FRAG. NO:1829) (SEQ. ID NO: 1842) 5'-OCCGGCGCGGGCG-3' (FRAG. NO:1830) (SEQ. ID NO:1843) 5'-GCCTGGGCTGGCC-3' (FRAG. NO: 1831) (SEQ. ID NO: 1844) TGGCCG-3' (FRAG. NO:1832) (SEQ. ID NO: 1845) GGG TOG CCO UTG TGO OCO 0-3' (FRAG. NO:1833) (SEQ. ID NO: 1846) 'TT CCT UTG COG TC-3' (FRAG. NO:1260)(SEQ. ID NO:1269) 0CC COG GCT CCG GOT G-3 (FRAG. NO: 1261)(SEQ. ID NO: 1270) 5'-CCC 0CC CGC CCG CCG GCC GCC GC-3' (FRAG. NO:1262)(SEQ. ID NO:1271) GCC 000 CTG TCC CCG CCC COC CCC-3' (FRAG. NO: 1263)(SEQ. ID NO: 1272) CCG GGG CGC GOG GG-3' (FRAG. NO:1264)(SEQ. ID NO:1273) CCC TCC CGC CCC TCT GG-3' (FRAG. NO:1265)(SEQ. ID NO:1274) GGC GCG GGC GTC GG-3' (FRAG. NO:1266)(SEQ. ID NO:1275) 5'-CCO CTC GCG CCT GGG GTU CCC TCT CCT CCC CCT GTG C-3' (FR.AG. NO:1267)(SEQ. ID NO:1276) TGC CTC U-G CTC TrC-3' (FRAG. NO:1268)(SEQ. ID NO:1277) GTC COC TGC CT- CTC CC-3 (FRAG. NO:1269)(SEQ. ID NO:1278) TCC TCG GCC GTT GCC TGT GC-3' (FRAG. NO:1270)(SEQ. ID NO:1279) CCG TCC TGT CGC CCT TCC GTG GTG C-3' (FRAG. NO:1I271)(SEQ. ID NO: 1280) 5'-TGT TGT CTC UTC TGC CCT C-3 (FRAG. NO:1272)(SEQ. ID NO:1281) GTG CTG GTG CTG GTG GTG GTG-3 (FRAG. NO:1273)(SEQ. ID NO:1282) CTG CCC GTG CTC GCC-3 (FRAG. NO:1I274)(SEQ. I D NO: 1283) CCT OGG CTG GCC TCT TCG GGT-3 (FRAG. NO: 1275)(SEQ. ID NO: 1284) GCT UrG GGG CTC TCT TGG UTG CCC 'IT-3(FRAG. NO:1276)(SEQ. ID NO:1285) 5'-CUT CTC GTG 0TG CCT CTC CTC CCT G0C U-G GTC GT-3' (FRAG. NO: 1277)(SEQ. ID NO: 1286) TOT CTG GGG TGG TGC TCC TCT CCC-3' (FRAG. NO:1278)(SEQ. ID NO: 1287) CCC TGC TGG CCG TTiT GT-3 (FRAG. NO: 1279)(SEQ. ID NO: 1288) OTI' UC TOT CUF CCT CT-3'(FRAG. NO:1280)(SEQ. ID NO:1289) CTC CTG 'TIr CTC CGT-3 (FRAG. NO:1281)(SEQ. ID NO: 1290) 5'-TUG OCT TOC TGC U-G CGG GOC TGT CTC C-3' (FRAG. NO: 1282)(SEQ. ID NO: 1291) GCC CCT GTG GOC 'liT CCC-3'(FRAG. NO:1283)(SEQ. ID NO:1292) TCC GOT CUT CTC CUT GGG GGT C-3' (FRAG. NO: I284)(SEQ. ID NO: 1293) CUT CUT GT GO CTG-3' (FRAG. NO:1285)(SEQ. ID NO:1294) COT CTG TCT =II TCC UTC C-3' (FRAG. NO:1286)(SEQ. ID NO:1295) 5'-TOO 000 TOO CCG UTG TOG OCO OTO TOG TCC 0CC T-3' (FRAG. NO:1287)(SEQ. ID NO:1296) *5'-TOC CTC TOC TOG TCT UTC-3' (FRAG. NO:1288)(SEQ. ID NO:1297) Human Interleukin-8* Fragments Antisense Oligonucleotide Fragments 5'-GBTG'ITGU- BCCBBBGCBT CBBGBBTBGC 'TI'GCTBTCT BBGGBTCBCB 'TJ7BGBCBTB GGBBBBCGCT GTBGGTCBGBB BGBTGTOCU- BCCU-CBCBC BGBGCTGCBG BBBTCBGGBBGG CTOCCBBOBGBG CCBCGGCCBOC 40 UTGBOTCBT GT[-BCBCBC BGTGBOOTGC TCCGGTGOCT 'I=GCTTGT GTGCTCTGCT GTCTCTG UTC CU-CCGOTOG MTITCCTG GCTCU7GTCC TICTCT-GG CCCU-GGCCC-3' (FRAG. NO:1834) (SEQ. ID NO:1847) 5'-0CTC CGG-3- (FRAG. NO:1835) (SEQ. ID NO:1848) 5'-CBBGBBTBOC-3- (FRAG. NO:1836) (SEQ. ID NO:1849) BGTGBG0TGC-3' (FRAG. NO:1837) (SEQ. ID NO:1850) 5'-BCCBBBGCBT CBBGBBTBGC-3- (FRAG. NO:1838) (SEQ. ID NO:1851) CCBCGGCCBGC-3- (FRAG. NO:1839) (SEQ. ID NO:1852) *5'-GTG CTC COG TOO CUT UT-3' (FRAG. NO:1289)(SEQ. ID NO:1298) 5'-OCT TOT GTO CTC TGC TOT CTC TG-3 (FRAG. NO:1290)(SEQ. ID NO:1299) CUT CCG GTO GUT TCT TCC TOG CTC UTG TCC T-3 (FRAG. NO:1291)(SEQ. ID NO:1300) 5-UTC TCT TOG CCC UTG 0CC C-3' (FRAG. NO:1292)(SEQ. ID NO:1301) BCBGB BGBBCT1GTTTBGBCC 'TTTBGBCBTB GOBBBBCGCT UTGGBGTCBT GTIBCBCBC BOTOBOOTOCTCCGGTGGCT TITGCT-OT-3- (FRAG. NO:1840) (SEQ. ID NO:1853) Human IL-8 Receptor Alpha Antisense Oligonucleotide Frag~ments 5'-ACAGGGGCTO TAATCUTCATC TGCAOGTGOC ATGCCAGTGA AATITAGATC ATCAAAATCC CACATCTGTG GATCTGTAAT ATIT7GACATG TCCTCYTCAG 'ITCAGCAAT GGT-1TGATCT AACTGAAGCA CCGGCCAGGB CBOGGGCTGT BBTCUTCBTC TGCBGGTGGC BTGCCBGTGB BBTBOBTC BTCBBBBTCC CBCBTCTGTG GBTCTGTBBT BTTTGBCBTG TCCTCUFCBG 'TTrCBGCBB TGGITGBTC TBBCTGBBGC BCCGGCCBGG TGGCTCGGTG CUTCTGCCCC TTOGCG GCGCTCGGUT O0TGTGGCCC CTGTGGTGCT TCGMIICCCC CTC'TrCTCT U7GU-COGOG GU-CUTGG CGGGCTGCU- GTCTCOU-CC-3' H:\Gabriela\Kcep\Speci\93951I-98.doc 05/07/02 (FRAG. NO:1841) (SEQ. ID NO:1854) 5'-CBOGGGC-3' (FRAG. NO:1842) (SEQ. ID NO:1855) 5'-GCBGGTGGC-3' (FRAG. NO:1843) (SEQ. ID NO:1856) 5'-GCGGCGCTC-3 (FRAG. NO: 1844) (SEQ. ID NO: 1857) 5'-TGGCTCGGTGCT-CTGCCCC (FRAG. NO:1293)(SEQ. ID NO:1302) Y-TGTTGTTGCGGCGCTC (FRAG. NO:1294)(SEQ. ID NO:1303) (FRAG. NO:1295)(SEQ. ID NO:1304) (FRAG. NO:1296)(SEQ. ID NO:1305) 5'-CCCTC1TJCTCTTGT-C (FRAG. NO: 1297)(SEQ. ID NO: 1306) 5'-GGG-TCTTGTGGC (FRAG. NO:1298)(SEQ. ID NO:1307) (FRAG. NO:1299)(SEQ. ID NO:1308) TAATCTTCATC TGCAGGTGGC ATGCCAGTOA AATIrAGATC ATCAAAATCC CACATCTGTG GATCTOTAAT ATrOACATG TCCTCTTCAG 'ITCAGCAAT GGTTTrGATCT AACTGAAOCA CCGGCCAOG-3' (FRAG.

NO:1845) (SEQ. ID NO:1858) 5'-B CBGGGGCTGT BBTCT7CBTC TGCBGGTGGC BTGCCBGTGB BBTT-rBGBTC BTCBBBBTCC CBCBTCTGTG GBTCTGTBBT Bn7GBCBTG TCCTC'rrCBG 'ITCBGCBB TGGTTT-GBTC TBBCTGBBOC BCCGGCCBGG-3' (FRAG.

NO:1846) (SEQ. ID NO:1859) Human GM-CSF Antisense Oli2onucleotide Fragments BBGCTCTGGO GCBGGGBGCT GGCBOGGCCC BGGGOGTGG CYI7CCTGCBC TGTCCBGBGT GCBCTOTGCC BCBGCBGCBG CTGCBOGGCC BTCBGCYI7CB TGGGGCTCTG GGTGGCBGGT CCBGCC!BTGG GTCTOOOTGG GGCTGGOCTG CBGGCTCCGG GCGOTCCBGCCBTGGGTCTG GOCTOOG CTGCBOOCTC CGGGCGGGCG GGTGCGGGCT GCGTGCTGOO GGCTGCCCCG CAOOCCC!TGC GGTCCBGCCB TGGGTCTGOG GGCTGGGCTG CBOGCTCCGO GCOGGCOGGT GCOOGCTGCO TGCTGGGGGC TGCCCCGCAG GCCCTGC-3' (FRAG.

NO:1847) (SEQ. ID NO: 1860) 5'-OBGCBGG BBO-3' (FRAG. NO:1848) (SEQ. ID NO: 1861) 5'-GCCBCBGCBGCBGC-3' (FRAG. NO:1849) (SEQ. ID NO: 1862) TGC GGG C-3- (FRAG. NO:1850) (SEQ. ID NO: 1863) CCB GCC BTGGGTCTOGGO-3 (FRAG. NO:1300)(SEQ. ID NO:1309) GCT GCB GGC TCC GG-3' (FRAG. NO:I3OI)(SEQ. ID NO:1310) 5-OCG GGCGO TGC GGG CTG CGT OCT GGG-3' (FRAG. NO:1302)(SEQ. ID NO:1311) TG CCC GCA GGC CCT GC-3' (FRAG. NO:1303)(SEQ. ID NO:l3I2) BBGCTCTGGG GCBOOGBGCT GGCBGGGCCC BGGGOOGTGG CUTCCTGCBC TGTCCBGBGT GCBCTOTGCC! BCBGCBGCBG CTGCBGOOCC BTCBGCTTCB TGGGGCTCTG OOTGGCBGOT CCBGCCBTGO GTCTGGGTGO GGCTGGGCTO CBGGCTCCGG GC-3' (FRAG. NO:1851) (SEQ. ID NO: 1863) 35 Human Tumor Necrosis Factor a Antisense Oligonucleotide Fragments :5'-GCBCCGCCTO GBGCCCTGGG GCCCCCCTGT CTrCTTGGGG BGCGCCTCCT CGGCCBGCTC CBCGTCCCGG BTCBTOCTTT CBGTGCTCBT GGTGTCC'IM CCBGGGGBOB GBGGCTOO TCCTCTGCTO TCCUOGCTOG TGCTCBTOGT GTCCITCCG CCCTGGGOCC! CCCCTGTCT7 CT-rGGOOCCT CT-rCCCTCTG GOOCCGTCT CTCTCCCTCT CTGCGTCTC TCTCTCTC TCTCTCTCTT CCCCTTCCC! GCTCT1CTG TCTCGGTGTC TGGT1TCTC TCTCCGCTGG CTGCCTGTCT GGCCTGCGCT CTTGGCCTGT GCTGFCCTC CTCCGGTTCC TGTCCTCTCT GTCTGTCGCC CCCTCTGGGG TCTCCCTCTG 0. OTGGTOOTC TrG~fl7CTrOOGGCTOOOCTC CTTCTCCB GTGCTCBTGG TGTCCGCTGB GOOBGCGTCT TGGGGCCTCT TCCCTCTGGG GGCCGTCTC TCTCCCTCTC UTGCGTCTCT CTCM~CTCT CTCTCTCTTC CCC'rrCCCG CTCYITCTGT CTCGGTGTCT GGT1ICTCT CTCCGCTGOC TGCCTGTCTG GCCTGCGCTC T7GGCCTOTG CTOU-CCTCC TCCGGT-CCT GTCCTCTCG TCTGTCOCCC CCTCTGGGOT CTCCCTCTGO CGTGOTGOTC TrO'rrOCTrG GGCTGGGCTC *:COTGTCTCCB GTGCTCBTGG TGTCCOCTGB GGGBGCGTCT GCTGGC-3' (FRAG. NO:1852) (SEQ. ID NO: 1865) *.5'-GGOOCCCCCC-3- (FRAG. NO:1853) (SEQ. ID NO:1866) 000 GGC CG TCT-3'(FRAG. NO:1854) (SEQ. ID NO:1867) GBGGGGCTGG-3' (FRAG. NO:1855) (SEQ. ID NO:l868)CGCBCC BGTCG BTCBGCTT CBGGCTCT GGGTC=CCBGOOGBGB GBGGG-3' (FRAG. NO:1304) (SEQ. IDNO:1313) GOT CCT CTG CTG TCC! T-rG CTG GTG CTC BTG OTO TCC! T-Fr CC GCC CTG GGG CCC CCC TOT CUF CTT GGG G **CCT CTr CCC TCT GGGOOOC CG TCT CTC TCC CTC TCT TGC GTC TCT C TCT TrC TCT CTC TCT CTUCCC C1TM CCC OCT CUT TCT GTC TC GGT GTC TOO TTlT TCT CTC TCC GCT GGC TGC CTG TCT GGC CTG CGC TCT T GGC CTG TGC TOT TCC TCC TCC GOT TCC TGT CCT CTC TOT CTO TC 0CC CCC TCT GGG OTC TCC CTC TGG C GTO OTO OTC Tro 'ITG CUT 000 CTG GOC TCC GTG TCT C CBO TGC TCB TOG TGT CCJ3 (FRAG. NO:1305) (SEQ. ID NO:1314) OBO GOB OCO TCT OCT GOC OCT GOT CCT CTO CTG TCC! Tr CTO OTO CTC BTO OTO TCC UTT CC 0CC CGG 000 CCC CCC TOT CUT CT 0000G CCT CUr CCC TCT 000 GOC CO TCT CTC TCC CTC TCT TG OTC TCT C TCT UTC TCT CTC TCT CUT CCC C TT CCC OCT CUT TCT OTC TC GOT OTC TOO T7 TCT CTC TCC OCT GOC TOC CTG TCT GOC CTO COC nj ~H:\Gabricla\Kcep\SpcciW93951-98.doc 05/07/02 0 TCT T GGC CTG TGC TOT TCC TCC TCC GGT TCC TGT CCT CTC TGT CTG TC 0CC CCC TCT GOG GTC TCC CTC TGG C GTO OTG GTC 17G 'TOG Crr GOG CTO GGC TCC GTG TCT C CBG TOC TCB TOG TGT CC OCT OBO GGB GCG TCT GCT GGC-3' (FRAG. NO:1306) (SEQ. ID NO:1315) GOT CCT CTO CTO TCC TTG CTG-30 (FRAG. NO:1655) (SEQ. ID NO:1664) 5'-OTO CTC BTO OTO TCC Trr CC-3' (FRAG. NO:1656)(SEQ. ID NO:1665) CTO 000 CCC CCC TOT CUT CTT 000 0-3' (FRAG. NO:1657)(SEQ. ID NO:1666) CUT CCC TCT 000 GOC CO-3' (FRAG. NO:1658)(SEQ. ID NO:1667) CTC TCC CTC TCT TOC OTC TCT C-3- (FRAG. NO:1659)(SEQ. ID NO:1668) TTC TCT CTC TCT CUT CCC C-3' (FRAG. NO:1660)(SEQ. ID NO:1669) 5*-T CCC OCT CT TCT OTC TC-3E3 (FRAG. NO:1661)(SEQ. ID NO:1670) GTC TOO IT? TCT CTC TCC-3' (FRAG. NO:1662)(SEQ. ID NO:1671) GOC TOC CTG TCT GOC CTG COC TCT T-3' (FRAG. NO:1663)(SEQ. ID NO:1672) CT TOC TOT TCC TCC-3' (FRAG. NO:1664)(SEQ. ID NO: 1673) TOTCCT CTC TOTCTG TC-3' (FRAG. NO:1665)(SEQ. ID NO:1674) 5'-0CC CCC TCTG000 TC TCC CTC TGC-3- (FRAG. NO:1666)(SEQ. ID NO:1675) TO OTCUGTUG CTT-3' (FRAG. NO:1667)(SEQ. ID NO:1676) 5'-000CTO OC TCC OTOTCT C-3' (FRAG. NO:1668)(SEQ. ID NO:1677) TOC TCB TOG TOTCC-3' (FRAG. NO:1669)(SEQ. ID NO:1678) OBO GB COTCT OCT OOC-3- (FRAG. NO:1670)(SEQ. ID NO:1679) Human Leukotriene C4 Synthase Antisense Oligonucleotide Fragments OCGCTCGBBC TCGOTGOOC COOTOOTOBO CGOCGGCOBCB COCOOBBOOC CcTGCGCOCC OBOBTCBCCTO CBGOOBOBBO TBGGCTTGCB OCBOOBCTCC CBOOBGOTG BCBGCBOCC!B OTBOBOCTBC CTCOTCCU-C BTOGTBCCGT COOTOTOOTO GCBCOOOCTG TOTOTOBBOG CGBGCTGOOC CCCOTCTOCT OCTCCTCGTG CCOCCTCOTC CTTCA TOO TA CCGTCOGTOT GOTGGCCTCO GOTGOCCOG TOOTOGOGCO CGCGCOCTCO COTGGCTCCO GCTC11TC1TTT CCCOGCTCCOT COOCCCGGOO OCCUOFGTCT CCCTCOTCCT TCBTOOTBCC G-3- (FRAG. NO:1856) (SEQ ID NO: 1869) OCBOOBC-3' (FRAG. NO:1857) (SEQ ID NO: 1870) 5'-CCCOOCTCCO-3' (FRAG. NO:1858) (SEQ ID NO: 1871) OCC-3' (FRAG. NO:1859) (SEQ ID NO: 1872) 5'-CB COCOG-3' (FRAG. NO:1860) (SEQ ID NO: 1873) CCG TCT OCT OCT CCT COT 0CC 0-3- (FRAG. NO:1307)(SEQ. ID NO:1316) COT CCT TCA TOO TAC COT COO TOT GOT OOC-3' (FRAG. NO:1308)(SEQ. ID NO:1317) 000 TOO 0CC GOT GOT 0-3' (FRAG. NO: I309)(SEQ. ID NO: 1318) 5-000 COC OCO COC TCO COT-3' (FRAG. NO:1310)(SEQ. ID NO:1319) 35 5-GOC TCC GOC TCT TCT UTC CCO OCT CCO TCO 0CC COO 000 CCT TOG TCT C-30 (FRAG.NO:131 I)(SEQ.ID NO:1320) COT CCT TCB TOG TBC CO-3' (FRAG. NO:1312)(SEQ. ID NO:1321) OCOCTCGBBC TCGOOTGOGC COOTOOTOBO COGCGOCGBCB COCOOBBOOC CCTOCOCOCC GBBCCT CBGBGB :BGTrC CGBTC BGGGGBBCG GTBOBOCTBC .40 Human Endothelin-1 Antisense Oligonucleotide Fragments 5'-BCCOOCOOBO CCGCCBGOGT OOBCTGGGBO TGGMTCTC CCCOGCCOTTC TCBCCCBCCO COCTGBGCTC BOCGCCTBBO BCTGCTGYI CTOGBOCTCC T-GGCBBOCC BCBBBCBGCB GBOBGBBBBT CBTGBGCBBB TBBTCCBU-C TOBBBBBBBG GGBTCBBBBB CCTCCCGU-C CCCG17CGCC TOOCGCGCOC TGCGOOUrCC TCGTGGGTTr CTCCCCOCCO UTCTCCGGTC TGTUGCCT[ OTGOCUTCT TOTCTTIT GCTGT-rCI TCCTGCTrGG CGTC'TMCC! TYrCTr-GTG CTCOOU-GTG OOTCCOCTOO TCC1TI7CCC TGTOTO'IMC TGCTOCCCOT TCGCCTOGCO COCOCTOCOG GUrCCTCOTO GGTTTCTCCC CGCCOUTCTC CGOTCTGTTO CCTTTGTGGG CTUCTrOTCT TTOGCTOT TC'IICCTO CUOOGCOTCT T~CCTTCT UOGTGCTCGG TOTOOOTCC GCTGOTCCUr TOCCCTOTOT OTTCTOCTG-3' (FRAG. NO:1862) (SEQ. ID NO:1875) CCGCCBOOGT GGBC-3' (FRAG. NO:1863) (SEQ. ID NO:1876) V 50 5'-CCOCCBOOO-3' (FRAG. NO:1864) (SEQ. ID NO:1877) 5'-OGCGCOCOC-3' (FRAG. NO:1865) (SEQ. ID NO:1878) 5'-GTOOOTCCOC-3' (FRAG. NO:1866) (SEQ. ID NO:1879) 5'-CCCOUTCOCCTOGCOC-3' (FRAG. NO:1313)(SEQ. ID NO:1322) 5'-OCOCTOCGOOU7CCTC-3' (FRAG. NO:1314)(SEQ. ID NO:1323) 5'-OTOOOTTCTCCCCOCCOTrCTC-3- (FRAG. NO:1315)(SEQ. ID NO:1324) 5'-CGGTCTGTTGCC1TI7GTGGG -3 (FRAG. NO:1316)(SEQ. ID NO:1325) 5'-CTTCT[OTC1TFITOCT-3' (FRAG. NO:131 7)(SEQ. ID NO:1326) 5'-OU'C1TTrCCTOCU-GOC-3' (FRAG. NO:I318)(SEQ. ID NO:1327) 5'-OTC=IICCTUrC'T-3' (FRAG. NO:1319)(SEQ. ID NO:1328) 5'-TOTOCTCOOGTOOOGGTC-3' (FRAG. NO:1320)(SEQ. ID NO:1329) 5'-COCTOGTCCT'T-TGCC-3' (FRAG. NO:1321)(SEQ. ID NO: 1330) H:\Gabricla\Keep\Spc?93951I-98.doc 05/07/02 58 5'-CTGTGTGTTrCTGCTG-3' (FRAG. NO:1322)(SEQ. ID NO:1331) 5'-CCCGT-rCGGGTGGCGC-3' (FRAG. NO:1323)(SEQ. ID NO:1322) 5'-GCGCTGCGGGTfrCCTC-3' (FRAG. NO:1324)(SEQ. ID NO:1323) 5'-GTGGGTfCTCCCCGCCGTTCTC-3' (FRAG. NO:1325(SEQ. ID NO:1324) 5'-CGGTCTGTTGCC=rGTGGG-3' (FRAG. NO:1326)(SEQ. ID NO:1325) 5'-CTrC1TGTCTmTGGCT-3' (FRAG. NO:1327)(SEQ. ID NO:1326) 5'-GT-rCTICCTGCTTGGC-3' (FRAG. NO:1328)(SEQ. ID NO:1327) 5'-GTCrrrCCT-CTr-3' (FRAG. NO:1329)(SEQ. ID NO:1328) 5'-TGTGCTCGGTTGTGGGTC-3' (FRAG. NO:1330)(SEQ. ID NO:1329) 5'-CGCTGGTCC1=GCC-3' (FRAG. NO:1331)(SEQ. ID NO:1330) 5'-CTGTGTGTCTGCTG-3' (FRAG. NO:1332)(SEQ. ID NO:1331) Endothelin Receptor ET-B Antisense Oligonucleotide Fragments GCGGGAAGCC TCTCTCCTCT CCCCAGATC CGCGACAGGC CGCAGGCAAG AACCAGCGCA ACCAGGGCGC GTCCGCACAG ACTfGGAGGC GGCTGCATGC TGCTACCTGC TCCAGAAGCG TCCGGTGGCC GCCGCGCC CTGTCGGGCG GGBBGCCTCT CTCCTCTCCC CBGBTCCGCG I3CBGGCCGCB GGCBBGBBCC BGCGCBBCCB GGGCGCGTCC GCBCBGBCTT GGBGGCGGCT GCBTGCTGCT BCCTGCTCGGGCG GGBBGCCTCCG GTGGCCGCCG CGCGTCCGGT GGCCGCCGCG CCTCTCTCCT CTCCCCGTGG CCCTGTCGGG CGGGTCCTGC CGTCCTGTCT CCi-rCrrr TGCTGTCTrG TCTTCCCGTC TCTGCTI-3' (FRAG. NO: 1867) (SEQ. ID NO: 1880) GGBBGCC-3' (FRAG. NO: 1868) (SEQ. ID NO: 1881) 5'-CGGGCGGG-3' (FRAG. NO: 1869) (SEQ. ID NO: 1882) 5'-CCGCBCBGBC-3' (FRAG. NO: 1870) (SEQ. ID NO: 1883) 5'-GCGTCCGGTGGCCGCCGC-3' (FRAG. NO:1333)(SEQ. ID NO:1342) 5'-GCCTCTCTCCTCTCCCC-3' (FRAG. NO:1334)(SEQ. ID NO:1343) 5'-GTGGCCCTGTCGGGCGGG-3' (FRAG. NO:1335)(SEQ. ID NO:1344) 5Y-TCCTGCCGTCCTGTCTCC'Tf-3' (FRAG. NO:1336)(SEQ. ID NO:1345) 5'-TC1TfGCTGTCTTGT-3' (FRAG. NO:1337)(SEQ. ID NO:1346) 5'-CT-fCCCGTCTCTGCTIT-3' (FRAG. NO:1338)(SEQ. ID NO:1347) GCGGGAAGCC TCTCTCCTCT CCCCAGATC CGCGACAGGC CGCAGGCAAG AACCAGCGCA ACCAGGGCGC GTCCGCACAG ACTTGGAGGC GGCTGCATGC TGCTACCTGC TCCAGAAGCG TCCGGTGGCC GCCGC-31 (FRAG. NO: 1871) (SEQ. ID NO: 1884) GCGGGBBGCC TCTCTCCTCT CCCCBGBTCC GCGBCBGGCC GCBGGCBBGB BCCBGCGCB BCCBGGGCGC GTCCGCBCBG BCTTrGGBGGC GGCTGCBTGC TGCTBCCTGC TCCBGBBGCG TCCGGTGGCC GCCGC-31 (FRAG. NO: 1872) (SEQ. ID NO: 1885) Endothelin ETA Receptor Antisense Oligonucleotide Fragments 5'-GTCTGTCCTC CCCGTCTCCT CCCACTGCT CTCCCGGGGG CTTrCCCCGGC TTCGGGTGGC CGGTGTCCCG CCCTTGTGCT GCYTTGCT TGTrFCCG'rrC TGGCTGCTCC GGTCTGTG1T GTGGTrG'T TGTTTCTrCT TGGGTGTGGG CCTTGCGGTr TI1GGCTGTGG GCCC1TTTGGG GCCTTGGCTT CTGGCTCGTC TGTCCTCCCC GTCTCCTCCC ACTGC'rrCT CCCGGGGGCT TCCCCGGC'rr CGGGTGGCCG GTGTCCCGGG CTCCGGCGCG GCGGCGGCTT CGGCTGCGGG TGGGTGGCGC GGGCTGCCGG GTCCGCGCGG CGCCTGGGCC CTTGTGCTGC TITIGCT~rG TICCGYI7CTG GCTGCTCCGG TCTGTGTrGT GGTGTIFG TIT7CTrCTTG GGTGTGGGCC T-rGCGGTIT GGCTGTGGGC CCTITGGGGC CT-rGGCTI7CT GGCTCCAT CCACATGATT GCTrAGATrr GTGCTGTATC TCTCAGGATT ATCACTGATr ACACATCCAA CCAGTGCCAG CCAAAAGGAT GCCCTGAGGC AAAGGGTC CATCT-fGAGG CAAATTGAG GACBTCCBC BTGBTFrGCTf BGBTTGTGC TGTBTCTCTC BGGB1TBTCB CTGBT-rBCBC BTCCBBCCBG TGCCBGCCBB BBGGBTGCCC TGBGGCBBBG GGTTTCCBTC TITGBGGCBBB ITTGBGGB-3- (FRAG. NO:1873) (SEQ. ID NO: 1886) 5'-GBGGCBBBGGG-3' (FRAG. NO:1874) (SEQ. ID NO: 1887) BBGGB-3' (FRAG. NO:1875) (SEQ. ID NO: 1888) C-3' (FRAG. NO:1876) (SEQ. ID NO: 1889) 5'-GTCTGTCCTCCCCGTCTCCTCCC-3- (FRAG. NO:1339)(SEQ. ID NO:1348) 50 5 -ACTGCTTCTCCCGGGG-3' (FRAG. NO:1340)(SEQ. ID NO:1349) 5'-GCfTCCCCGGCTI'C-3' (FRAG. NO:1341)(SEQ. ID NO:1350) 5'-GGGTGGCCGGTGTCCCGGGCTCCGGCGCGGCGGC-3' (FRAG. NO:1342)(SEQ. ID NO:I351) 5'-GGCTTCGGCTGC-3- (FRAG. NO:1343)(SEQ. ID NO:1352) S'-GGGTGGGTGGCGCGG-3' (FRAG. NO:1344)(SEQ. ID NO:1353) 5'-GCTGCCGGGTCCGCGCGGCGCCTGGGCC-3' (FRAG. NO:1345)(SEQ. ID NO:1354) 5'-C-17GTGCTGC=m--3' (FRAG. NO:1346(SEQ. ID NO:1355) 5'-TGC'17Gl7CCGTTC-3' (FRAG. NO:1347)(SEQ. ID NO:1356) -TGGCTGCTCCGGTCTGTGTGTGGlGTMG-3' (FRAG. NO:1348)(SEQ. ID NO:1357) H:\Gabricla\Keep\Speci93951-98doc 05/07/02 5'-MTrCTrGGGTGTGGG-3' (FRAG. NO:1349)(SEQ. ID NO:1358) 5'-CCTTGCGGTIMGG-3- (FRAG. NO:1350)(SEQ. ID NO:1359) 5'-CTGTGGGCCCTrG-3- (FRAG. NO:1351)(SEQ. ID NO:1360) 5'-OGGCCTJTGGCT-fCTGGCTC-3' (FRAG. NO:1352)(SEQ. ID NO:1361) 5'-CATCCACATG AT-FGCT-rAGA M~GTGCTGT ATCTCTCAGG ATrATCACTG A'FrACACATC CAACCAGTGC CAGCCAAAAG GATGCCCTGA GGCAAAGGGT TTCCATCTTG AGGCAAAT17T GAGGA-3' (FRAG. NO:1353) (SEQ. ID NO:1362) BYI7GCTJ7BGB TTTGTGCTGT BTCTCTCBGG BTTBTCBCTG BTTBCBCBTC CBBCCBGTGC CBGCCBBBBG GBTGCCCTGB GGCBBBGGGT TTCCBTCYI7G BGGCBBBTf GBGGB-3- (FRAG. NO:1354) (SEQ. ID NO:1363) Substance P Antisense Oligonucleotide Antisense Oligonucleotide Fra2ments TFGGGTCTCC GGGCGBTFCT CTGCBGBBGB TGCTCBBBGG GCTCCGGCBG 'FrCCTCCTrG BTCTGGTCGCT GTCGTBCCBG TCGGBCCBGT BBTTCBGBTC BTCBTJ7GGCT CCTBM~CTT CTGCBBBCBG CTGBGTGGBG BCBBGBBBBB BGBCTGCCBB GGCCBCGBGG BTITTCBTGT TGGBTrF7GC GBCGGBCBGT CCCGCGGGGT GCTGAG1TFC TCTGGT-rCCT CCGBGCGCBC GTGGTCGCTC CGCGMTCTC TGGTTrCCTCC GGTCCCGCGG GGTGCTGTCT GGTCGCTGTC GTGGCT7GGG TCTCCGGGCG GIMCCT[rCC YTTMCCGC-3- (FRAG. NO:1877) (SEQ ID NO: 1890) GGGCGB-3' (FRAG. NO:1878) (SEQ ID NO: 1891) 5'-GGCCBCGBGG-3' (FRAG. NO:1879) (SEQ ID NO: 1892) 5'-GGGTCTCCGGGCG-3' (FRAG. NO:1880) (SEQ ID NO: 1893) TCTCCGGGCG G-3' (FRAG. NO:1881) (SEQ ID NO:1894) 5'-CGTGGTCGCTCCGC-3' (FRAG. NO:1355)(SEQ. ID NO:1364) 5'-GTrCTCTGG1TCCTCCG-3' (FRAG. NO:1356)(SEQ. ID NO:1365) 5'-GTCCCGCGGGGTGCTG-3' (FRAG. NO:1357)(SEQ. ID NO:1366) 5'-TCTGGTCGCTGTCGT-3' (FRAG. NO:1358)(SEQ. ID NO:1367) 5'-GGCTTGGGTCTCCGGGCG-3' (FRAG. NO:1359)(SEQ. ID NO:1368) 5'-GTrrCC'rrCCTrCCGC-3' (FRAG. NO:1360)(SEQ. ID NO:1369) TTrGGGTCTCC GGGCGBTFCT CTGCBGBBGB TGCTCBBBGG GCTCCGGCBG TTCCTCCT7G BTCTGGTCGCT GTCGTBCCBG TCGGBCCBGT BBTTCBGBTC BTCBT7GGCT CCTBTTJTCT[ CTGCBBBCBG CTGBGTGGBG BCBBGBBBBB BGBCTGCCBB GGCCBCGBGG BYTMCBTGT TGGB=1TGC GBCGGBCBGT CCCGCGGGGT GCTGAG'TTC TCTGGTfCCT CCGBGCGCB-3' (FRAG. NO:1882) (SEQ ID NO: 1895) Substance P Receptor Antisense Oligonucleotide Fra2ments GBTCCBCBTC BCTBCCBCGT TGCCCBCCBC BGBGGTCBCC BCBBTGBCCG TGTBGGCBGC TGCCCBBBGG BCBBTrTGCC BGGCTGGTI7G CBCGBBCTGB TTGGGTrCCG BGGTGTTBGT GGBGBTGTr GGGGBGBGGT CTGBGTCCBC CGGGBGGBCG TI7BTCCBTT-r CGBBGCTBGG CGGTBBBGCC CTBCTBTCTG TBCBCBBCCC CCCTCTGCBG CBGBGTCCTG *****TCGTGGCGCC TGGGGCTCBG GGTCCGGGC TAAGATGATC CACATCACTA CCACGTfGCC CACCACAGAG GTCACCACAA 35 TGACCGTGTA GGCAGCTGCC CAAAGGACAA TTTGCCAGGC TGGTTGCACG AACTGATTGG GTrCCGAGGT GTrAGTGGAG ATG3TTGGGG AGAGGTCTGA GTCCACCGGG AGGACGTTAT CCAT-1'CGAA GCTAGGCGGT AAAGCCCTAC TATCTGTACA .CAACCCCCCT CTGCAGCAGA GTCCTGTCGT GGCGCCTGGG GCTCAGGGTC CGTCCTGTCG TGGCGCCTGG GGCTCTrCTr :TrGTGGGCTC TIGGTGGCT GTGGCTGTGG TCTCTGTGGT TGCTGCCCTG GGTCTGGGGG TGTGGCC1TG GGGCCGTCCT CTGGCTCCTC CTCGTGGGCC CCC-3' (FRAG. NO:1883) (SEQ. ID NO:1896) 409 5-GGGBGGBCG-3' (FRAG. NO:1884) (SEQ. ID NO:1897) 5'-GGGTC CG-3' (FRAG. NO:1885) (SEQ. ID NO:1898) 9. 5-GGGCC CCC-3' (FRAG. NO:1886) (SEQ. ID NO:1899) 5'-GTCCTGTCGTGGCGCCTGGGGCTC-3- (FRAG. NO:1361)(SEQ. ID NO:I370) 5'-TTCTI=GTGGGCT-3- (FRAG. NO:1362)(SEQ. ID NO:1371) 5'-CTGGTGGCTGTGGCTG-3' (FRAG. NO:1363)(SEQ. ID NO:1372) 5'-TGGTCTCTGTGGTrG-3' (FRAG. NO:1364)(SEQ. ID NO:1373) :5'-CTGCCCTGGGTCTGG-3' (FRAG. NO:1365)(SEQ. ID NO:1374) 5'-GGGTGTGGCCTITGGGGCCGTCCTCTGGCTCCTCCTCGTGGGCCCCC (FRAG. NO:1366)(SEQ. ID NO:1375) GATCCACATC ACTACCACGT TGCCCACCAC AGAGGTCACC ACAATGACCG TGTAGGCAGC TGCCCAAAGG ACAA1TTGCC AGGCTGGTrG CACGAACTGA T-rGGGT-rCCG AGGTGTlAGT GGAGATGT-17 GGGGAGAGGT CTGAGTCCAC CGGGAGGACG TrATCCATC GAAGCTAGGC GGTAAAGCCC TACTATCTGTA CACAACCCCC CTCTGCAGCA GAGTCCTGTC GTGGCGCCTG GGGCTCAGGGTCC-3' (FRAG. NO:1367) (SEQ. ID NO: 1376) GBTCCBCBTC BCTBCCBCGT TGCCCBCCBC BGBGGTCBCC BCBBTGBCCG TGTBGGCBGC TGCCCBBBGG BCBBTTTGCC BGGCTGGT-7G CBCGBBCTGB TGGGTrCCG BGGTGTTBGT GGBGBTG1TF GGGGBGBGGTC TGBGTCCBCC 55 GGGBGGBCGT TBTCCBnI7C GBBGCTBGGC GGTBBBGCCC TBCTBTCTGTB CBCBBCCCCC CTCTGCBGCB GBGTCCTGTC GTGGCGCCTG GGGCTCBGGG TCC-3' (FRAG. NO:1368) (SEQ. ID NO: 1377) Chymase Antisense Oligonucleotides Antisense Oigonuclcotide Fragments CTGCBGATr CBGBGGGBBG BBCCCTGBTB CTCBCCBGCT TCBGCTCTGG BGCBCBBGBG BBBGBGCBGC BGGGGGBGBG GBBGBBGCBG CBTCT7CCCB GBGBGGCTGC CTGBGCBBBT GCTGGTITC CTCCBGTC YrGGGYFMB z J-j Q. H:\Gabtiela\Keep\Speci9395 I-98.doc 05/07/02 TBBCTCCCBG BBGGCBBGBG BGGGGCBBGG CGTTTrCTFC TCTCGCTGGT 1TTCCTTTCC TGGCAGTGGG TGGGGGTGGG GGTGGGGTGG CT-rCCT-rGTT CCTGGGGGTG TCCTCTrGCT CTGGGC=r~ CTCCCCYTM CCT-rCCTGTC TGTM~CCTG GGGCTCTrCCT CTGTCTCTGT GTCCT-rGCCC TGGCCCTCTf CCCTCTCCTG TCTCCTGTCC CTGTGT-rCCG CCCGTC'rrCC CTCTCCTGAC CTCCTMCC TCCGCTGGGT GGGGCCCTGC CTGTITCTCTG CTCCCTGGCT TGGGGMTCT TCTGTGTGTC TTC'FrCCTCT GT-rGGCTGGC TfCTCCTI7C TrIfrGTCTrC CTGGGTGCCC CrTrCCcrr TCTfGGGTCC TTGGTGCTTG GGCTGGG-3' (FRAG. NO:1887) (SEQ. ID NO:1900) 5'-GGBGCBCBBG-3- (FRAG. NO:1888) (SEQ. ID NO:1901) 5'-GBBGCBGC-3- (FRAG. NO:1889) (SEQ. ID NO:1902) CG-3' (FRAG. NO:1890) (SEQ. ID NO:1903) 5'-CGT1TCTTCTCTC-3' (FRAG. NO:1369)(SEQ. ID NO:1378) 5'-GCTGG1TIrTCC1TTCC-3- (FRAG. NO:1370)(SEQ. ID NO:1379) 5'-TGGCAGTGGGTGGGGGTGGGGGTGGGGTGGC-3' (FRAG. NO:1371)(SEQ. ID NO:1380) 5'-TITCCTrGTlTCCTGGGGGTGTCCT-3 (FRAG. NO:1372)(SEQ. ID NO:1381) 5'-CT17GCTCTGGGCTMlCT-3 (FRAG. NO: 1373)(SEQ. ID NO: 1382) 5'-CCCCYTI'CC-fl7CC-3 (FRAG. NO: I 374)(SEQ. MD NO: 1383) 5'-TGTCTGTMlCCTGGGG-3 (FRAG. NO: 1375)(SEQ. ID NO: 1384) 5'-CTCTCCTCTGTCTCTGTGT-3 (FRAG. NO: I 376)(SEQ. ID NO: 1385) 5'-CCTI7GCCCTGGCCC-3' (FRAG. NO: I 377)(SEQ. ID NO: 1386) 5'-TCTrCCCTCTCCTGTCTCCTGT-3 (FRAG. NO: 1378)(SEQ. ID NO: 1387) 5'-CCCTGTGTTCCGCCC-3 (FRAG. NO:1I379)(SEQ. ID NO: 1388) 5'-GTCT-rCCCTCTCCTG-3'(FRAG. NO: I 380)(SEQ. ID NO: 1389) 5'-ACCTCCTIrCCTCCG-3 (FRAG. NO: 138 1)(SEQ. ID NO: 1390) 5'-CTGGGTGGGGCCCTG-3 (FR-AG. NO: I 382)(SEQ. ID NO: 1391) 5'-CCTGT-fCTCTGCTCCC-3'(FRAG. NO: I 383)(SEQ. ID NO: 1392) 5'-TGGCT-FGGGG1T1CTTCTG-3' (FRAG. NO: I 384)(SEQ. ID NO: 1393) 5'-TGTGTCTTC-rrCCTCTGT-r-3 (FRAG. NO: I 385)(SEQ. ID NO: 1394) 5'-GGCTGGCTTI'CTCCT-rC-3 (FRAG. NO: 1386)(SEQ. ID NO: 1395) 5'-TITrGTCT-rCCTGGG-3' (FRAG. NO: I387)(SEQ. ID NO: 1396) 5'-TGCCCCT-rC'FCC'ITTC'rGGG-3' (FRAG. NO: 1388)(SEQ. ID NO: 1397) 5'-TCCT-rGGTGCTGGGCTGGG-3 (FRAG. NO:1I389)(SEQ. ID NO: 1398) CTGCBGAT CBGBGGGBBG BBCCCTGBTB CTCBCCBGCT TCBGCTCTGG BGCBCBBGBG BBBGBGCBGC BGGGGGBGBG GBBGBBGCBG CBTCT-rCCCB GBGBGGCTGC CTGBGCBBBT GCTGGTITC CTFCCBGTC TITGGGTITIB TBBCTCCCBG BBGGCBBGBG BGGGGCBBGG-3- (FRAG. NO:1891) (SEQ. ID NO:1904) Endothelal Nitric Oxide Synthase Antisense Oligonucleotide Fragments *.0:35 5'-GCGTCYI7GGG GTGCBGGGCC CBTCCTGCTG CGCCTGGGCG CTGCTGTGCG TCCGTCTGCT GGGGGGCCGG GGTGGCTGGG CCCTGCTTGC CGCACGACCC CGGGCCGACC CGAGGCTCGG GGGGCTGTGT TCTGGCGCTG GTGGGCTTFGG GCCCCTCTGG 0000 CTGGGGGTGC CTGTGGCTGC CGGITGCCCC GGTrGGTGGC GCCGTCCTGC TGCCGGTCGT TGGCTGGGTC CCCCCGCCCG TTTCCTGGGG TCCGCGTGGG GTGCTCCGGT TCCTCGTGCC GCTGCTGCCT TGTC'IMCCG GCCGTGGCGG CGTGGTGGTC CGCCCCCCCT GGCCTTCTGC TCGGGGTCTG GCTGGTTGCC GGTGCCCYUFG GCGGCGGTCT TCTTCCTGGT GGCTCTGGGC *CCGGCCGGTC TCGGGCGTCT CGTGT[CGCT CTTGTGCTGT TCCGGCCGCT CCTTCCTCYIT CCGCCGCCGC CGCTCCCCGC CCGCTCGTCG CCCTGGCCCG GCCTCCTCCT GGCCGCTGTC TCGGGCGGCG GCCTITGGCGC TCCGTITrGGG GCTGCCTCTG 00GCGCYrCCGG CCCTCGGCCT GGGCGCTCTC T-rCCGCCTGT GCTGGTGGCC CTCGTGGGCC CCTCCTGGCC TCCGGTGTCC TGTGGTCCCC CGGCTGGTGG CCGGGCCGGT TGGGCGGGCG TGGGCGCCGG CGGGTCCTCC GGGCTGCCCT TCTCCGCCGG GGGTCCCGCG CTCCTGCTGT TCCCTGGGCT CTrCTGCCTC TCTCCTGGGT GGGTGCTGGG TGCCGGGGTC TCCGGGC'rrG CCCCGCGCTG CTGGGCGYTC TGCGGTCT-rG GGGTrGTCTG TGGCCCCGCT CGTGTCGCCC TCCGTCGCCC GTCGCCGGCC TCGTCCCCTC CTGGGTGCGC GGCGGGCTGG TCCTGGCGT7 T-rGCTCCITFC CTGGGCGTCT TGGGGTGCBG GGCCCBTCCT GCTGCGCCTG GGCGCTGCTG TGCGTCCGTC TGCTGGGGGG CCGGGGTGGC TGGGCCCTGC TTGCCGCACG ACCCCGGGCC GACCCGAGGC TCGGGGGGCT GTGTTCTGGC GCTGGTGGGC TTGGGCCCCT CTGGGGGCTG GGTFITCCTGC TGCGCCTGGG CGCTGGCGTC T-rGGGGTGCG GGGCCGGGGG GCCGGGGGGC CGCTG117CGT GGGCCTGGGG GTGCCTGTGG CTGCCGGTrG CCCCGGTTGG TGGCGCCGTC CTGCTGCCGG TCGTF7GGCTG GGTCCCCCCG CCCG1TCCT GGGGTCCGCG TGGGGTGCTC *CGGTT1CCTCG TGCCGCTGCT GCCTGTCT11 TCCGGCCGTG GCGGCGTGGT GGTCCGCCCC CCCTGGCCTr CTGCTCGGGG TCTGGCTGGT TGCCGGTGCC CTTGGCGGCG GTCTrCTTCC TGGTGGCTCT GGGCCCGGCC GGTCTCGGGC GTCTCGTGYT CGCTCTTGTG CTGTrCCGGC CGCTCCYI7CC TCT-rCCGCCG CCGCCGCTCC CCGCCCGCTC GTCGCCCTGG CCCGGCCTCC 055 TCCTGGCCGC TGTCTCGGGC GGCGGCC'rrG GCGCTCCGtr TGGGGCTGCC TCTGGCGCTT CCGGCCCTCG GCCTGGGCGC 00*TCTCTTCCGC CTGTGCTGGT GGCCCTCGTG GGCCCCTCCT GGCCTCCGGT GTCCTGTGGT CCCCCGGCTG GTGGCCGGGC CGGTITGGGCG GGCGTGGGCG CCGGCGGGTC CTCCGGGCTG CCCTrCTCCG CCGGGGGTCC CGCGCTCCTG CTGT-rCCCTG GGCTCr'rCTG CCTCTCTCCT GGGTGGGTGC TGGGTGCCGG GGTCTCCGGG CYITGCCCCGC GCTGCTGGGC GT-rCTGCGGT CTTGGGGT-TG TCTGTGGCCC CGCTCGTGTC GCCCTCCGTC GCCCGTCGCC GGCCTCGTCC CCTCCTGGGT GCGCGGCGGG CTGGTCCTGG CGYIGCTC CTfCCTGG-3- (FRAG. NO:1892) (SEQ. ID NO:1905) 5'-GCGGGGCCG-3- (FRAG. NO:1893) (SEQ. ID NO: 1906) 5'-CGGGGGGC-3- (FRAG. NO:1894) (SEQ. ID NO: 1907) H:\Gabiela\Keep\Spec?'\93951-98.doc 05/07/02 5'-GCGCGGCGGGC-3' (FRAG. NO:1895) (SEQ. ID NO: 1908) (FRAG. NO:1390)(SEQ. ID NO:1399) GGGGCCGGGGTGGCTGGGCCCTGC1TGCCGC (FRAG. NO: 139 1)(SEQ. ID NO: 1400) ACGACCCCGGGCCGACCCGAG (FRAG. NO: I 392)(SEQ. ID NO: 140 1) GCTCGGGGGGCTGTGTTCTGGCGCTGGTGGG (FRAG. NO: 1393)(SEQ. ID NO: 1402) CY-FGGGCCCCTCTGGGGGCTGGGTr (FRAG. NO: I 394)(SEQ. ID NO: 1403) TCCTGCTGCGCCTGGGCGCTG (FRAG. NO: I 395)(SEQ. ID NO: 1404) GCGTCTTGGGGTGC (FRAG. NO: I 396)(S EQ. ID NO: 1405) GGGGCCGGGGGGCCGGGGG (FRAG. NO: 1397)(SEQ. MD NO: 1406) GCCGCTGTTCGTGGGCCTGGG (FRAG. NO:1I398)(SEQ. ID NO: 1407) GGTGCCTGTGGCTGCC (FRAG. NO: I 399)(SEQ. ID NO: 1408) GGYITGCCCCGGTITGGTGGC (FRAG. NO: I400)(SEQ. ID NO: 1409) GCCGTCCTGCTGCCGGT (FRAG. NO: 140 1)(SEQ. ID NO: 14 CGTITGGCTGGGTCCCCCCGC (FRAG. NO: I 402)(SEQ. 11) NO: 1411) CCG1TI7CCTGGGGTCC (FRAG. NO:I1403)(SEQ. ID NO: 1412) GCGTGGGGTGCTCC (FRAG. NO: 1404)(S EQ. ID NO: 1413) GGYI7CCTCGTGCCG (FRAG. NO: 1405)(SEQ. ID NO: 1414) CTGCTGCCTTGTCT1-TCC (FRAG. NO: 1406)(SEQ. ID NO: 1415) GGCCGTGGCGGCGTGGTGGTCC (FRAG. NO: I 407)(SEQ. ID NO: 1416) GCCCCCCCTGGCCT-rCTGCTC (FRAG. NO: 1408)(SEQ. ID NO: 1417) GGGGTCTGGCTGGT (FRAG. NO:I1409)(SEQ. ID NO: 1418) TGCCGGTGCCCT-rGGCGGC (FRAG. NO: 141 0)(S EQ. ID NO: 1419) GGTCTTCT-7CCTGGTG (FRAG. NO:I141 1)(SEQ. ID NO: 1420) GCTCTGGGCCCGGCCGGTCTCGG (FRAG. NO: 141 2)(SEQ. ID NO: 142 1) GCGTCTCGTGT-rCG (FRAG. NO: 1413)(SEQ. ID NO: 1422) CTC117GTGCTGTI7CCGGCCG (FRAG. NO: 14 I4)(SEQ. ID NO: 1423) CTCCTTCCTCTrCCGCCGCC (FRAG. NO: 14I5)(SEQ. ID NO: 1424) GCCGCTCCCCGCCC (FRAG. NO: 141 6)(SEQ. ID NO: 1425) GCTCGTCGCCCTGGCCC (FRAG. NO: 14I7)(SEQ. ID NO: 1426) GGCCTCCTCCTGGCCGC (FRAG. NO:14I48)(SEQ. ID NO: 1427) TGTCTCGGGCGGCGGCCTFGGC (FRAG. NO: 14 19)(SEQ. ID NO: 1428) GCTCCG7ITGGGGCTG (FRAG. NO: I420)(SEQ. ID NO: 1429) CCTCTGGCGC'I17CC (FRAG. NO: 142 1)(SEQ. ID NO: 1430) GGCCCTCGGCCTGGGCGCTC (FRAG. NO: 1422)(SEQ. ID NO: 143 1) TC-17CCGCCTGTGC (FRAG. NO: 1423)(SEQ. ID NO: 1432) TGGTGGCCCTCGTGG (FRAG. NO: 1424)(SEQ. ID NO: 1433) GCCCCTCCTGGCCTCCGGTGTCC (FRAG. NO: I 425)(SEQ. ID NO: 1434) *TGTGGTCCCCCGGCTGGT (FRAG. NO: 1426)(SEQ. ID NO: 1435) 9 GGCCGGGCCGG17GGGCGGGC (FRAG. NO:1I427)(SEQ. ID NO: 1436) GTGGGCGCCGGCGGGTCCTCC (FRAG. NO: 1428)(SEQ. ID NO: 1437) GGGCTGCCCTTCTCC (FRAG. NO: I 429)(SEQ. ID NO: 1438) V.900 GCCGGGGGTCCCGC (FRAG. NO:I1430)(SEQ. ID NO: 1439) GCTCCTGCTGTTCCCTGGGCTCT-fCTGCC (FRAG. NO: 143 1)(SEQ. ID NO: 1440) TCTCTCCTGGGTGGGTGCTGGGTGCCG (FRAG. NO: 1432)(SEQ. ID)NO: 1441) GGGTCTCCGGGCTI'G (FRAG. NO: 1433)(SEQ. ID NO: 1442) CCCCGCGCTGCTGGGCGT-FCTGC (FRAG. NO: 1434)(SEQ. ID) NO: 1443) GGTCTTGGGGYITGTC (FRAG. NO: 1435)(SEQ. ID NO: 1444) TGTGGCCCCGCTCG (FRAG. NO: I436)(S EQ. ID NO: 1445) TGTCGCCCTCCGTCGCC (FRAG. NO:1I437)(SEQ. ID NO: 1446) CGTCGCCGGCCTCGTCC (FRAG. NO: 1438)(SEQ. ID NO: 1447) CCTCCTGGGTGCGC (FRAG. NO:1439)(SEQ. ID NO:1448) 99...GGCGGGCTGGTCCT (FRAG. NO:1I440)(SEQ. ID NO: 1449) GGCGTFITGCTCCTI7CCTGG (FRAG. NO: 144 1)(SEQ. ID NO: 1450) 5'-GCGTCTTGGGGTGCBGGGCCCBTCCTGCTGCGCCTGGGCGCTG-3' (FRAG. NO:1896) (SEQ. ID NO: 1909) to: 55 Inducible Nitric Oxide Synthase Antisense Oligonucleotide Fragments TrGBTCCT CBCBTGCCGT GGGGBGGBCB BTGGCTGCCT CCCCGGGGT-r TCTGCTGCTT GCTGCTTrC' TCCCGTCTCC C'rClTrrCCC GTCTCCTY[ TGCCTCTTG GGTITCCTGT-F GT17CTGGCC TGCTI7GGTGG CGCTT1GTGC GTCCTCTC TCTrCTCTTG GGTCTCCGCT TCTCGTCCTG CCT1T7CCTG TCTCTGTCGC GCCGTTCCTC CTCCGGCGTC CTCCTGCCCT GTGCTGTrG CCTCGGGTGG TGCGGGTCCC GGTGCTCCCC CGGCGGGCCG GCTGGT-TGCC TGGGCCTGTC TGGTGGGGTG TGGGGCCGCT GGGT-rGGGGG TGTGGTGGGC TCTTCTGTGG CCTGTGGGGC TGTrGGTGTC TCTGTGGGCG TGTGCTGGGT C'FrGGGGCTT CCTCCCT-rGT GCTGGGTGCG GCCTCCCCGC CCCCCTrCTG GGCCGGTGGC CTGGCTCCT[ GTGGGCGCTI' CTGGCTCTI7G CCCTGTCCTTr CTTCGCCTCG TGGCTGCTGG GCTGC-3' (FRAG. NO:1897) (SEQ. ID NO:1910) H:\Gabriela\Keep\Speci\93951 -98.doc 05/07/02 5'-CCCCGGGG-3- (FRAG. NO:1898) (SEQ. ID NO: 1911) 5'-GGGGCCGCTGGG-3' (FRAG. NO:1899) (SEQ. ID NO:1912) 5'-GGGGGTGTGG-3- (FRAG. NO:1900) (SEQ. ID NO: 1913) 5'-CTGCCTCCCCGGGGT-3' (FRAG. NO:1442)(SEQ. ID NO:1451) 5'-'rCTGCTGCTrGCTG-3- (FRAG. NO: 1443)(SEQ. ID NO: 1452) 5'-CTTCTITCCCGTCTCC-3 (FRAG. NO:1444)(SEQ. ID NO:1454) 5'-C'TCTTTCCCGTCTCC-3 (FRAG. NO:1445)(SEQ. ID NO:1453) 5'-T1rMGCCTCTITrG-3- (FRAG. NO:1446)(SEQ. ID NO:1455) 5'-GGrfCCTG1TG1TI7CT-3' (FRAG. NO:1447)(SEQ. ID NO:1456) 5'-GGCCTGCTfTGGTGGCG-3 (FRAG. NO:1448)(SEQ. ID NO:1457) 5'-GCTTGTGCGI-rCC-3' (FRAG. NO:1449)(SEQ. ID NO:1458) 5'-TCTCTCTrTCTC-rGGGTCTCCGC-rrCTCGTCCTGCC-3' (FRAG. NO:1450)(SEQ. ID NO:1459) 5'-TMCCTGTCTCTGTCGC-3' (FRAG. NO:1451)(SEQ. ID NO:1460) 5'-GCCGT-rCCTCCTCC-3' (FRAG. NO:1452)(SEQ. ID NO:146I) 5'-GGCGTCCTCCTGCCC-3' (FRAG. NO:1453)(SEQ. ID NO:1462) 5'-TGTGCTGTITGCCTCGG-3' (FRAG. NO: 1454)(SEQ. ID NO: 1463) 5'-GTGGTGCGGGTCCC-3'(FRAG. NO: 1455)(SEQ. ID NO: 1464) 5'-GGTGCTCCCCCGGC-3' (FRAG. NO: I456)(SEQ. ID NO: 1465) 5'-GGGCCGGCTGGYI7GCCTGGGC-3- (FRAG. NO: I 457)(SEQ. ID NO: 1466) 5'-CTGTCTGGTGGGGTGTGGGGCC-3- (FRAG. NO: 145 8)(SEQ. ID NO: 1467) 5'-GCTGGGTTGGGGGTGTGGTG-3 (FRAG. NO: I 459)(SEQ. ID NO: 1468) 5'-GGCTCTTCTGTGGCC-3' (FRAG. NO: I 460)(SEQ. ID NO: 1469) 5'-TGTGGGGCTGT-rGGTG-3' (FRAG. NO: 146 1)(SEQ. ID NO: 1470) 5'-TCTCTGTGGGCGTGTG-3' (FRAG. NO: 1462)(SEQ. ID NO: 147 1) 5'-CTGGGTCTrGGGGCTrrC-3 (FRAG. NO: 1463)(SEQ. ID NO: 1472) 5'-CTCCCTfGTGCTGGG-3' (FRAG. NO: 1464)(SEQ. ID NO: 1473) 5'-TGCGGCCTCCCCGC-3' (FRAG. NO: 1465)(SEQ. ID NO: 1474) 5'-CCCCCT-FCTGGGCC-3 (FRAG. NO: 1466)(SEQ. ID NO: 1475) 5'-GGTGGCCTGGCTCCT[GTGG-3 (FRAG. NO: 1467)(SEQ. ID NO: 1476) 5'-GCGCT-fCTGGCTCTTG-3 (FRAG. NO: 1468)(SEQ. ID NO: 1477) 5'-CCCTGTCCTFrCTI'CGCCTCGT-3' (FRAG. NO: 1469)(SEQ. ID NO: 1478) 5'-GGCTGCTGGGCTGC-3' (FRAG. NO: I 470)(SEQ. ID NO: 1479) 5'-CTGCCCCBG1TTIGBTCCTCBCBTGCCGTGGGGBGGBCBBTGG-3' (FRAG. NO:1901) (SEQ. ID NO:1914) NF-kB Antisense Oligonucleotide Frajments 5'-CGGCCCTTCT CACTGGAGGC ACCGGGCAGT CCTCCATGGG AGGGITrGGGC TI'GGCCGGGG CTGCCCGGTG CCTCCTC1TG GCTGGTCCCT CGT[GTCCT GGGCCCCGC TCCCGCTGCT CGGCCTCCGT G'rrCMrGGC CTCTfGCTCC GCCTGCTGTC TTGTCCCGTC CCCTCCTCGC T-rGCGT1T7CC CTCTTCC17G TCTCCAGGC CYI7CCTCCGC T-FCCGCTGCT GGGGCCCGCG CCGGGGGGGC GCTCGGCTCC GCGGCTTCCT CCCCGGCTGG GGGGTCCTGG TCTCCGGGGC CTGCGGCTCG CGGGCTCGGG GCTGCGTGCG CCGCGCGCGG CGTCCGCGGT GGGTGGCGCT GTCCCGCCGT 40 GGTGTGTCTC CGTrCTCGTC CTGCGCCGTC CTGGTCTGCC CGTGGGGTCC TGGGCGTGGT GGGGGGCGTC TGGTGCCTCG TCTGCCCCGT GGGGCTrCGG GCTCGGGGCT GTTFCGTCCCC CCTGCCGCTC TGTGGCCTCC GGGGCTCCTC GTI=CGCTG CYFCGGGTGT CCT-rCTCGGC GTGTGGCCCC GGGTCCCGGC CCTGCTGGGC TGGGCGGGGT CGCTGCCCTG GGCT7CTGGC CCGTCTGGTT GTCTGTCGGT GCT-FGTCTCG GGT~CTGGC CTCTGTGCTG GGCGCT-rCTC TGCCTCCTGC TCCGCCCTCC TGGTGGCTCG GCTGGGGGTG CCCGTGCGGG GGTGGGTGTG 45 GGGTGT1T7C GGGGTCCTCC CCTrCCC-3 (FRAG. NO: 1902) (SEQ. ID NO: 1915) 5'-GGGCGGGGTCGC-3 (FRAG. NO:1903) (SEQ. ID NO:1916) 543GCGCCGTCC-3 (FRAG. NO:1904) (SEQ. ID NO:1917) 5'-GGGCGTGGTGG-3' (FRAG. NO:190S) (SEQ. ID NO:1918) 5'-GTrGGGC~rGGCCGGGG-3 (FRAG. NO: 147 1)(SEQ. ID NO: 1480 5'-CTGCCCGGTGCCTCC-3 (FRAG. NO: 1472)(SEQ. ID NO: 148 1) 5'-TCTITGGCTGGTCCCTCGT-3 (FRAG. NO: 1473)(SEQ. ID NO: 1482) 5'-TGTCCYFGGGCCCC-3 (FRAG. NO: I 474)(SEQ. ID NO: 1483) 5'-GCTCCCGCTGCTCGGCCTCCGT-3- (FRAG. NO: 1475)(SEQ. ID NO: 1484) 5'-GT-rC1TTGGCCTCFrGCTCC-3 (FRAG. NO: 1476)(SEQ. ID NO: 1485) 5'-GCCTGCTGTCTTlGTCC-3' (FRAG. NO: 1477)(SEQ. ID NO: 1486) 5.-CGTCCCCTCCTCGCTJ7GCGTTC-3 (FRAG. NO: 1478)(SEQ. ID NO: 1487) 5.-CCTCT-rCC1TGTC'FfCCA-3 (FRAG. NO: 1479)(SEQ. ID NO: 1488) 5.-GGCCTTCCTCCGCTTCCGCTGC-3 (FRAG. NO: 1480)(SEQ. ID NO: 1489) 5'-TGGGGCCCGCGCCGG-3 (FRAG. NO: 148 1)(SEQ. ID NO: 1490) 5'-GGGGGCGCTCGGCTCCGCGGC1TCCTCCCCGG-3' (FRAG. NO: I 482)(SEQ. ID NO: 1491) 5'-CTGGGGGGTCCTGG-3' (FRAG. NO: 1483)(SEQ. ID NO: 1492) 5!-TCTCCGGGGCCTGCGGCTCGC-3'(FRAG. NO: 1484)(SEQ. ID NO: 1493) -GGGCTCGGGGCTGCGTGCGC&3- (FRAG. NO: 1485)(SEQ. ED NO: 1494) S SSS H:\GabriclecaKp\Specd 9395l -98.doc 05/07/02 63 5'-GCGCGCGGCGTCCGCGGTG-3 (FRAG. NO: 1486)(SEQ. ID NO: 1495) 5'-GGTGGCGCTGTCCCGCC-3 (FRAG. NO: 1 487)(SEQ. ID NO: 1496) 5'-GTGOTGTGTCTCCGTTCTCGTCCTGCGCCGTC-3 (FRAG. NO: 1488)(SEQ. ID NO: 1497) 5'-CTGGTCTGCCCGTGG-3 (FRAG. NO: 1489)(SEQ. ID NO: 1498) 5'-GGTCCTGGGCGTGGTGG-3 (FRAG. NO: 1490)(SEQ. ID NO: 1499) 5'-GGGGCGTCTGOTGC-3 (FRAG. NO: 149 1)(SEQ. ID NO: 1500) 5'-CTCGTCTGCCCCGTG-3 (FRAG. NO: 1492)(SEQ. ID NO: 150 1) 5'-GGGCilCGGGCTCGG-3 (FRAG. NO: 1493)(SEQ. ID NO: 1502) 5'-GGCTGTlCGTCCCCCCTGCCGCTCTGTGGCCTCC-3 (FRAG. NO: 1494)(SEQ. ID NO: 1503) 5'-GGGGCTCCTCGrI=C-3' (FRAG. NO: 1495)(SEQ. ID NO: 1504) 5'-GCTGCilCGGGTGTCCU-CTC-3' (FRAG. NO: 1496)(SEQ. ID NO: 1505) 5'-GGCGTGTGGCCCCGG-3' (FRAG. NO: 1497)(S EQ. ID NO: 1506) 5'-GTCCCGGCCCTGCTGGGCTGGGCGGGGTC-3 (FRAG. NO: 1498)(SEQ. ID NO: 1507) 5'-OCTGCCCTGGGCT-CTGGCCCGTCT-3' (FRAG. NO: 1499)(SEQ. ID NOA 508) 5'-GGilGTCTGTCGGT-3 (FRAG. NO:1I500)(SEQ. ID NO: 1509) 5'-GCT[GTCTCGGGT-1?CTGG-3 (FRAG. NO: 150 1)(SEQ. ID NO: 15 5'-CCTCTGTGCTGGGC-3 (FRAG. NO: I 502)(SEQ. ID NO: 1511) 5'-GCT-rCTCTGCCTCCTGCTCC-3' (FRAG. NO: I 503)(S EQ. ID NO: 1512) 5'-GCCCTCCTGGTGGCTC-3 (FRAG. NO: I 504)(S EQ. ID NO: 1513) 5'-0GCTGGGGGTGCCCGTGCG-3' (FRAG. NO:1I505)(SEQ. ID NO: 1514) 5'-GGGGTGGGTGTGGGGTGTh-3 (FRAG. NO: I 506)(S EQ. ID NO: 1515) 5'-T-FCGGGGTCCTCCCCilCCC-3'(FRAG. NO: I 507)(SEQ. ID NO: 1516) 5'-CGGCCCilCTCACTGGAGGCACCGGGCAGTCCTCCATGGGAGG-3 (FRAG. NO:1906) (SEQ. ID NO:1919) Human Major Basic Protein Anti-sense Oligonucleotide Fragments 5'-Gil? TCA TCT TGG CiT TAT CCTCT CCC CUT Gil? CCT CCC CTCT CCT GCT CTG GRG TCT CCT C U-C CCT CCC TCC CCT GCC GTG ilG TCT GTG GGT GTC GUT TCG CTC ilG T1lG CCC TGG 0CC CU- CCC TGC TGG GGG GGA GUT TCA TCT TGG GUT TCB TCT TGG CUT TBT CCTCT CCC CUT Gil? CCT CCC CTCT CCT GCT CTG GRG TCT CCT C ilC CCT CCC TCC CCT GCC GTG U-G TCT GTG GGT GTC Gil? TCG CTC iT 'ITG CCC TGG GCC CU- CCC TGC TOG GGG 0GB GT-rTCB TCT TGG-3' (FRAG. ID:1907) (SEQ. ID NO:1920) 5'-OGG GGA GTTJ-3 (FRAG. ID:1908) (SEQ. ID NO:1921) CCC TGG GCC C-3' (FRAG. ID:1909) (SEQ. ID NO:1922) TCA TCT TGG CU1 TAT CC-3' (FRAU. NO:15O8) (SEQ. ID NO:1517) CCC CUr GUT CCT CCC C-3' (FRAU. NO:1509)(SEQ. ID NO:1518) CCT OCT CTG ORG TCT CCT C-3' (FRAG. NO:1510)(SEQ. ID NO:1519) 5'-ilC CCT CCC TCC CCT GCC-3 (FRAG. NO: 151 I)(SEQ. ID NO: 1520) TTG TCT OTG GOT GTC C-3' (FRAG. NO: 1512)(SEQ. ID NO: 152 1) TCG CTC UTG UTG CCC-3 (FRAG. NO:1I 5 I3)(SEQ. ID NO: 1522) 0 0...5'-TOG 0CC CUT CCC TGC TGG-3' (FRAG. NO: 1 514)(SEQ. ID NO: 1523) GGA GUT TCA TCT TGG-3' (FRAG. NO: 1515)(SEQ. ID NO: 1524) 5'-GTT TCA TCT TGO CUT TAT CCTCT CCC CUT GUT CCT CCC CTCT CCT GCT CTO ORG TCT CCT C UTC CCT CCC TCC :CCT 0CC GTG UTG TCT OTG GOT GTC GUT TCG CTC UTG iTOr CCC TGG 0CC CU7 CCC TGC TOG GOG GGA OUT TCA TCT TGG-3' (FRAU. ID:1910) (SEQ. ID NO:1923) TCB TCT TOG CUT TBT CCTCT CCC CTT GUT CCT CCC CTCT CCT OCT CTG ORG TCT CCT C U-C CCT CCC TCC CCT 0CC GTO iTO TCT OTG GOT GTC GUT TCO CTC iTO TTG CCC TOG 0CC CUT CCC TGC TOG GO 0GB GUT TCB TCT TGG-3' (FRAU. ID:1911) (SEQ. ID NO:1924) Human Eosinophil Major Basic Protein Fraements 5'-OGG 0GB OUT TCB TCT TGG CU- T-3'(FRAG. NO: I 516)(SEQ. ID NO: 1525) TCB TCT TGG CU-3' (FRAG. NO:1517)(SEQ. ID NO:1526) 5'-000 GOB GUr TCB TCT TOG CT-3' (FRAG. NO:1I5I8)(SEQ. ID NO: 1527) 50 5'-000 0GB GUT TCB TCT TOG C-3' (FRAG. NO: 15 19)(SEQ. ID NO: 1528) 5'-000 GOB GUT TCB TCT TOG-3' (FRAG. NO: I 520)(SEQ. ID NO: 1529) 5'-000 GOB GUT TCB TCT TG-3' (FRAG. NO: 152 I)(SEQ. H) NO: 1530) GOB GU- TCB TCT T-3 (FRAG. NO: 1522)(SEQ. ID NO: 153 1) 5'-000 GOB GU- TCB TCT-3' (FRAG. NO: I523)(SEQ. ID NO: 1532) 55 5'-000 GOB GUT TCB TC-3' (FRAG. NO:1I524)(SEQ. ID NO: 1533) 5'-000 GOB GTT TCB T-3 (FRAG. NO:1I525)(SEQ. ID NO: 1534) 5'-000 GOB GT-T TCB-3' (FRAG. NO: 1526)(SEQ. ID NO: 1535) GOB OUT TCB TCT TOG CUT T-3 (FRAG. NO: I 527)(SEQ. ID NO: 1536) 5'-00 GOB OU- TCB TCT TOG CUT-3 (FRAG. NO: I 528)(SEQ. ID NO: 1537) 5'-00 GOB OUT TCB TCT TOO CT-3 (FRAG. NO: 1529)(SEQ. ID NO: 1538) H:\Gabdiela\KCeep\SpecA939SI -98.doc 05/07/02 n \V 64 GGB GTT TCB TCT TOG C-3 (FRAG. NO: I 530)(SEQ. ID NO: 1539) GOB OTT TCB TCT TGO-3 (FRAG. NO: 153 1)(SEQ. ID NO: 1540) 0GB OTT TCB TCT TG-3' (FR-AG. NO:1I 532)(SEQ. ID NO: 154 1) 5'-00 0GB GTT TCB TCT T-3 (FRAG. NO: 1 533)(SEQ. ID NO: 1542) 5'-00 GGB GTT TCB TCT-3 (FRAG. NO:1I534)(SEQ. ID NO: 1543) GGB GTT TCB TC-3 (FRAG. NO: I 535)(SEQ. ID NO: 1544) GGB OTT TCB T-3 (FRAG. NO:1I536)(SEQ. IM NO: 1545) 0GB GTT TCB TCT TGG CTT T-3'(FR-AG. NO: 1 537)(SEQ. ID NO: 1546) GGB GTT TCB TCT TGG CTT-3'(FRAG. NO:1I538)(SEQ. ID NO: 1547) 5-G GGB OTIT TCB TCT TOG CT-3'(FRAG. NO: I539)(SEQ. ID NO: 1448) GOB GTT TCB TCT TOG C-3 (FRAG. NO: I540)(SEQ. ID NO: 1449) GOB OTT TCB TCT TGG-3 (FRAG. NO: 154 1)(SEQ. ID NO: 1550) GOB GTT TCB TCT TG-3 (FRAG. NO: I542)(SEQ. ID NO: 155 1) GOB GTT TCB TCT T-3 (FRAG. NO:1I543)(SEQ. ID NO: 1552) 5'-0 GOB OTT TCB TCT-3 (FRAG. NO: I 544)(SEQ. ID NO: 1553) GGB GYIT TCB TC-3' (FRAG. NO: 1 545)(S EQ. ID NO: 1554) GTT TCB TCT TOG CTTr T-3 (FR-AG. NO: I 546)(SEQ. ID NO: 1555) OTT TCB TCT TGG CTTF-3 (FRAG. NO: I 547)(SEQ. ID NO: 1556) OTT TCB TCT TOG CT-3'(FRAG. NO:1I548)(SEQ. ID NO: 1557) 5'-GOB OTT TCB TCT TOO C-3' (FRAG. NO: I 549)(SEQ. ID NO: 1558) S'-GOB OTT TCB TCT TGG-3 (FR-AG. NO: I 550)(SEQ. ID NO: 1559) OTT TCB TCT TG-3 (FRAG. NO: 155 1)(SEQ. ID NO: 1560) OTT TCB TCT T-3'(FRAG. NO: I 552)(SEQ. ID NO: 156 1) OTT TCB TCT-3' (FRAG. NO: I 553)(SEQ. ID NO: 1562) 5'-GB OTT TCB TCT TGO CTT T-3 (FRAG. NO: I 554)(SEQ. ID NO: 1563) OTT TCB TCT TOO CTT-3 (FRAG. NO:1I555)(SEQ. ID NO: 1564) OTT TCB TCT TOO CT-3 (FRAG. NO:1I556)(SEQ. ID NO: 1565) OTT TCB TCT TOO C-3' (FRAG. NO: I 557)(SEQ. ID NO: 1566) OTT TCB TCT TGO-3 (FRAG. NO: I 558)(SEQ. ID NO: 1567) 5'-GB OTTr TCB TCT TO-3' (FRAG. NO: I 559)(SEQ. ID NO: 1568) OTT TCB TCT T-3' (FRAO. NO: I 560)(SEQ. ID NO: 1569) OTT TCB TCT TOO CTT T-3 (FRAG. NO: 156 1)(SEQ. ID NO: 1570) OTT TCB TCT TOO CTT-3' (FRAG. NO:1I 562)(SEQ. ID NO: 157 1) OTT TCB TCT TOO CTTr-3' (FRAO. NO:1I563)(SEQ. ID NO: 1572) 5'-B OTT TCB TCT TOO CT-3 (FRAG. NO:1I564)(SEQ. ID NO: 1573) OTT TCB TCT TOO C-3' (FRAG. NO: I 565)(SEQ. ID NO: 1574) 5'-B OTT TCB TCT TOO-3' (FRAG. NO: I 565)(SEQ. ID NO: 1575) OTT TCB TCT TO-3' (FRAG. NO: I 567)(S EQ. ID NO: 1576) TCB TCT TOG CTT T-3' (FRAO. NO: I 568)(SEQ. D) NO: 1577) 4 0 5'-OTT TCB TCT TOO CT-r-3' (FRAG. NO: I 569)(S EQ. ID NO: 1578) TCT TGC- (R NO:1I 57OXSEQ. ID NO: 1579) 0 ~5'-OTT TCB TCT TOO (FRAG. NO:57)(SEQ. ID NO: 158) TCB TCT TOCT -3 (FRA. NO: 157)(SEQ. ID NO:158 5-TT TCB TCT TOG CT-rT-3- (FRAG. NO: 157)(SEQ. ID NO: 158) 5'-TT TCB TCT TOG CT-r3' (FRAG. NO: I 57)(SEQ. ID NO: 158) TCB TCT TGG C-3' (FRAG. NO:I57)(SEQ. ID NO: 158) TCB TCT TG C-3' (FRAG. NO: 57)(SEQ. ID NO: 158) TCB TCT TOG CT-rT-3' (FRAG. NO: 57)(SEQ. ID NO: 158) 5-T TCB TCT TOO GTT-3' (FRAG. NO: I57)(SEQ. ID NO: 158) 505'-TTCB TCT TG CTT-3 (FRAG. NO: I 58)(S EQ. ID NO: 158) TCT TOG CTT-3' (FRAG. NO:58)(SEQ. ID NO: 159) 5'-00GOTTCB TCT T OG CT T T-3 (FRAG. NO: 15 58)(SEQ. ID NO: 15 .5'-GOG GB OT TCB TCT TO CT- T-3' (FRAG. NO: 58)(SEQ. ID) NO: 156) 555'-0 GB OTT TCB TCT TG CTT T-3' (FRAG. NO: I58)(SEQ. ID NO: 156) 5-GOGB OTT TCB TCT TO CT T-3- (FRAG. NO: 158)(SEQ. ID NO: 154) OTT TCB TCT TG CTT T-3' (FRAG. NO: 158)(SEQ. ID NO: 155) OTT TCB TCT TO CTT T3 (FRAG. NO: I 58)(SEQ. ID NO: 150) TCB TCT TG CTF T-3' (FRAG. NO: I 58)(SEQ. ID NO: 157) 5-TT TCB TCT TO CT T-3' (FRAG. NO:58)(SEQ. ID NO: 157) 5-T- TCB TCT TO CT T-3' (FRAG. NO: I59)(SEQ. ID NO: 158) CB TCT TG CTT T-3' (FRAG. NO:59)(SEQ. D NO:158) TCT TOG CTT T-3' (FRAG. NO: I 592)(SEQ. ID NO: 160 1) _5-000 GOB OTT TCB TCT TOO CTT-3' (FRAG. NO:1I593)(SEQ. ID NO: 1526) H:\Gabtieta\Kcep\Spcf\9395 I-98.doc 05/07/02 GOB GTT TCB TCT TGG CTT-3' (FRAG. NO:1I594)(SEQ. ED NO: 1537) GGB GTT TCB TCT TGG CTT-3' (FRAG. NO: I 595)(SEQ. ID NO: 1547) GTT TCB TCT TGG CTT-3' (FRAG. NO: I 596)(SEQ. ID NO: 1556) OTT TCB TCT TOG CTr-3' (FRAG. NO:1597)(SEQ. ID NO:1564) 5'-B GTT TCB TCT TGG CM-3' (FRAG. NO: I598)(SEQ. ID NO: 157 1) TCB TCT TOG CTTr-3' (FRAG. NO:1599)(SEQ. ID NO:1578) TCB TCT TOO CTT-3' (FRAG. NO:I1600)(SEQ. ID NO: 1583) TCB TCT TGG CTT-3' (FRAG. NO: 160 1)(SEQ. ID NO: 1587) TCT TOG CTTr-3' (FRAG. NO: 1602)(SEQ. ID NO: 1590) 5'-GGG GOB OTT TCB TCT TOG CT-3' (FRAG. NO: 1 603)(SEQ. ID NO: 1527) GOB OTT TCB TCT TOO CT-3' (FRAG. NO: I 604)(SEQ. ID NO: 1538) GOB GTT TCB TCT TOO CT-3' (FRAG. NO: 1605)(SEQ. ID NO: 1548) GTT TCB TCT TOG CT-3' (FRAG. NO: I 606)(SEQ. ID NO: 1557) 0117 TCB TCT TOG CT-3' (FRAG. NO: I 607)(S EQ. ID NO: 1565) 5'-B 0117 TCB TCT TOO CT-3' (FRAG. NO: I 608)(SEQ. ID NO: 1573) TCB TCT TOG CT-3' (FRAG. NO: I609)(SEQ. ID NO: 1579) 5'-11 TCB TCT TOG CT-3' (FRAG. NO: 161 0)(S EQ. ID NO: 1584) TCB TCT TOO CT-3' (FRAG. NO: 161 I)(SEQ. ID NO: 1588) GOB OTT TCB TCT TGG C-3' (FRAO. NO: 1612)(SEQ. ID NO: 1528) 5'-OO GOB OTT TCB TCT TOO C-3' (FRAG. NO: 1613)(SEQ. ID NO: 1539) GOB OTT TCB TCT TOG C-3' (FRAG. NO: 1614)(SEQ. ID NO: 1549) OTT TCB TCT TOG C-3' (FRAG. NO: 161 5)(SEQ. ID NO: 1558) OTT TCB TCT TOG C-3' (FRAG. NO: I616)(SEQ. ID NO: 1566) OTT TCB TCT TOO C-3' (FRAO. NO: 1617)(SEQ. ID NO: 1574) 5'-OTT TCB TCT TOO C-3- (FRAG. NO: 1618)(SEQ. ID NO: 1580) TCB TCT TOO C-3' (FRAG. NO: I619)(SEQ. ID NO: 1585) GOB OTT TCB TCT TOG-3' (FRAO. NO: I 620)(S EQ. ID NO: 1529) 0GB OTT TCB TCT TOO-3' (FRAG. NO: 162 1)(SEQ. ID NO: 1540) OOB OTT TCB TCT TGG-3' (FRAG. NO: I 622)(SEQ. ID NO: 1550) 5'-GOB OTT TCB TCT TOG-3' (FRAG. NO: 1623)(SEQ. ID NO: 1559) OTT TCB TCT TOG-3' (FRAG. NO: 1624)(SEQ. ID NO: 1567) OTT TCB TCT TOO-3' (FRAG. NO:1625)(SEQ. ID NO:1575) TCB TCT TOO-3' (FRAG. NO:1626)(SEQ. ID NO:1581) 5'-000 GOB OTT TCB TCT TO-3' (FRAG. NO:1627)(SEQ. ID NO:1530) 5'-GG GOB OTTr TCB TCT TO-3' (FRAG. NO: 1628)(SEQ. ID NO: 1541) 0GB OTT TCB TCT TO-3' (FRAG. NO:1629)(SEQ. ID NO:1551) 5'-GOB OTT TCB TCT TG-3' (FRAG. NO:1630)(SEQ. ID NO:1560) OT-T TCB TCT TO-3' (FRAG. NO: 163 1)(SEQ. ID NO: 1568) 405'-B OTT TCB TCT TG-3' (FRAG. NO: 1632)(SEQ. 1I)NO: 1576) 5-000 GOB OTT TCB TCT T-3 (FRAG. NO: I 633)(SEQ. ID NO: 153 1) GOB OTT TCB TCT T-3 (FRAG. NO:1I634)(SEQ. ID NO: 1542) 5'-G GOB OTT TCB TCT T-3 (FRAG. NO: 1635)(SEQ. ID NO:I1645) GOB OTT TCB TCT T-3 (FRAG. NO:1I636)(SEQ. ID NO: 1552) OTT TCB TCT T-3' (FRAG. NO: 1637)(SEQ. ID NO: 156 1) 5'-GB OTT TCB TCT T-3- (FRAG. NO:1I638)(SEQ. ID NO: 1569) 5'-000 GOB OTT TCB TCT-3' (FRAG. NO:1I639)(SEQ. ID NO: 1532) GOB OTT TCB TCT-3 (FRAG. NO: 1640)(SEQ. ID NO:I1543) 5'-G GOB OTT TCB TCT-3' (FRAG. NO: 164 1)(SEQ. ID NO: 1553) OTT TCB TCT-3 (FRAG. NO: 1642)(SEQ. ID NO: 1562) 5'-GGG GOB OTT TCB TC-3' (FRAG. NO: I 643)(SEQ. ID NO: 1533) GOB OTT TCB TC-3' (FRAG. NO: 1644)(SEQ. ID NO: 1544) 0GB OTT TCB TC-3' (FRAG. NO: I 645)(SEQ. ID NO: 1554) 5'-000 GOB OTT TCB T-3 (FRAO. NO: 1646)(SEQ. ID NO: 1534) 5'-GO GOB OTT TCB T-3 (FRAG. NO: I 647)(SEQ. ID NO: 1545) :55 5-GOO GOB OTT TCB-3- (FRAG. NO: I 648)(SEQ. ID NO: 1535) CCC CTT OTT CCT CCC C-3' (FRAG. NO: I 649)(SEQ. ID NO: 1518) CCT OCT CTG OTO TCT CCT C-3' (FRAG. NO:1I650)(SEQ. ID NO: 1659) CCT CCC TCC CCT GCC-3' (FRAG. NO: 165 1)(SEQ. ID NO: 1520) TTO TCT OTO GOT OTC C-3' (FRAG. NO: 1652)(SEQ. ID NO: 152 1) 5s-OTT TCG CTC TTOG TTG CCC-3 (FRAG. NO: 1653)(SEQ. ID NO: 1522) 0CC CTT CCC TOC TGO-3' (FRAG. NO: 1654)(SEQ. ID NO: 1523) GOB 0-3- (FRAG. NO:1912)(SEQ. ID NO:1925) GOT OTC C-3' (FRAG. NO:1913) (SEQ. ID NO:1926) uj ~~,cv H:\Gabricla\Keep\SpecA 9395 I-98.doc 05/07/02 66 BP-1 Antisense Oligonucleotide Fragments BGTGGTGCTG CCCGTfrGBG GTBTGGCGCT CCBCCBBT-rC CCTfTCTCC T7GYM~CCG 'rrrCTCrGC CGTCTGTGGT T-3' (FRAG. NO:1914) (SEQ. ID NO:1927) 5'-CCCG1TfGBGGTBTGGC-3'(FRAG. NO:191 5) (SEQ. ID NO:1928) 5'-GCTCCBCCBBTrCCC=rrCTCC-3'(FRAG. NO:1916) (SEQ. ID NO:1929) 5'-TrGTInrCCG1TrCTCTTG-3'(FRAG. NO: 1917) (SEQ. ID NO: 1930) 5'-CCGTCTGTGGTT-3'(FRAG. NO:1918) (SEQ. ID NO:1931) 5'-CCCGMIGAGGTATGGC-3'(FRAG. NO:1919) (SEQ. ID NO:1932) 5'-GCTCCBCCAATTCCCTIMCTCC-3'(FRAG. NO:1920) (SEQ. ID NO:1933) CIEBP3 Antisense Oligonucleotide Fragments GGCC-3 (FRAG. NO:1921) (SEQ. ID NO:1934) GGC-3'(FRAG. NO:1922) (SEQ. ID NO:1935) GCCCCGCCGCCT17CTBGCCCCGG-3' (FRAG. NO:1923) (SEQ. ID NO:1936) 5'-GGGCCCBGCCCCGCCGCCTI=CTBGCCCCG-3 (FRAG. NO:1924) (SEQ. ID NO:1937) 5'-GGGCCCBGCCCCGCCGCCTTrCTBGCCCC-3' (FRAG. NO:1925) (SEQ. ID NO:1938) -GGGCCCBGCCCCGCCGCCTIMCTBGCCC-3 (FRAG. NO: 1926) (SEQ. ID NO: 1939) 5'-GGGCCCBGCCCCGCCGCCTrl1rCTBGCC-3 (FRAG. NO:1927) (SEQ. ID NO:1940) 5'-GGGCCCBGCCCCGCCGCCTrrCTBGC-3- (FRAG. NO:1928) (SEQ. ID NO:1941) 5'-GGGCCCBGCCCCGCCGCCrTrCTBG-3' (FRAG. NO:1929) (SEQ. ID NO:1942) 5'-GGGCCCBGCCCCGCCGCCrI=CTB-3- (FRAG. NO:1930) (SEQ. ID NO:1943) 5'-GGGCCCBGCCCCGCCGCCTI=CT-3' (FRAG. NO:1931) (SEQ. ID NO:1944) 5'-GGGCCCBGCCCCGCCGCCYTU-fC-3 (FRAG. NO:1932) (SEQ. ID NO:1945) 5'-GGGCCCBGCCCCGCCGCCTM~-3- (FRAG. NO:1933) (SEQ. ID NO:1946) 5'-GGGCCCBGCCCCGCCGCCTrr-3- (FRAG. NO: 1934) (SEQ. ID NO:1947) 5'-GGGCCCBGCCCCGCCGCCTh-3- (FRAG. NO:1935) (SEQ. ID NO:1948) 5'-GGGCCCBGCCCCGCCGCCT-3 (FRAG. NO:1936) (SEQ. ID NO:1949) 5'-GGGCCCBGCCCCGCCGCC-3' (FRAG. NO:1937) (SEQ. ID NO:1950) 5'-GGGCCCBGCCCCGCCGC-3 (FRAG. NO:1938) (SEQ. ID NO:1951) 5'-GGGCCCBGCCCCGCCG-3'(FRAG. NO:1939) (SEQ. ID NO:1952) 5'-GGGCCCBGCCCCGCC-3 (FRAG. NO:1940) (SEQ. ID NO:1953) 5'-GGGCCCBGCCCCGC-3' (FRAG. NO:1941) (SEQ. ID NO:1954) 5'-GGGCCCBGCCCCG-3 (FRAG. NO:1942) (SEQ. ID NO:1955) 5'-GGGCCCBGCCCC-3' (FRAG. NO:1943) (SEQ. ID NO:1956) 5'-GGGCCCBGCCC-3 (FRAG. NO:1944) (SEQ. ID NO:1957) 5-GCBCCGCCT:1CBCCGC3(RG O:95 SQ DN:98 *5'-GCCBGCCCCGCCGCCTCTBGCCCCGGC-3' (FRAG. NO: 194) (SEQ. ID NO: 199) S5'-CCBGCCCCGCCGCCTTCTBGCCCCGGC-3 (FRAG. NO:194) (SEQ. ID NO:196) 405'-CBGCCCCGCCGCCTrCTBGCCCCGGC-3' (FRAG. NO:19) (SEQ. ID NO:196) 5'-CGCCCCGCCGCCTICTBGCCCCGGC-3 (FRAG. NO:19) (SEQ. ID NO:196) 5'-CCCCGCCGCCTTCTBGCCCCGGC-3' (FRAG. NO:195) (SEQ. ID NO:196) 5'-GCCCGCCGCCTCTBGCCCCGGC-3(FRAG. NO:195) (SEQ. ID NO:196) S5'-CCCGCCGCCTCTBGCCCCGGC-3 (FRAG. NO: 195) (SEQ. ID NO: 196) 5'-CCGCCGCCTTrCTBGCCCCGGC-3 (FRAG. NO: 195) (SEQ. ID NO: 196) 5'-CGCCGCCTTCTBGCCCCGGC-3' (FRAG. NO:195) (SEQ. ID NO:196) 5-CCCGCCTrCTBGCCCCGGC-3' (FRAG. NO:195) (SEQ. ID NO:19) 5'-GCGCTI CTBGCCCCGGC-3 (FRAG. NO:19) (SEQ. ID NO:19 5'-CCGTI17CTBGCCCCGGC-3' (FRAG. NO:19) (SEQ. ID NO:197) V00.0: 5'-CGTrrCTBGCCCCGGC-3 (FRAG. NO:19) (SEQ. ID NO:1971 0 5'-GCTMrCTBGCCCCGGC-3 (FRAG. NO:19) (SEQ. ID NO:197 5'-CTTrCTBGCCCCGGC-3' (FRAG. NO:196) (SEQ. ID NO:197) 5'-TrCTBGCCCCGGC-3- (FRAG. NO:196) (SEQ. ID NO:197) 5'-TCTBGCCCCGGC-3 (FRAG. NO:196) (SEQ. ID NO:197) 5'-GCGBGGCTGTCBCCTCGCTGGGCCC-3 (FRAG. NO:1967) (SEQ. ID NO:1980) H:\Gabriela\Kce\SpciV93951I-98.doc 05/07/02 rv 67 5'-GCGBGGCTGTCBCCTCGCTGGGCC-3' (FRAG. NO:1968) (SEQ. ID NO: 1981) 5'-GCGBGGCTGTCBCCTCGCTGGGC-3- (FRAG. NO:1969) (SEQ. ID NO:1982) 5'-GCGBGGCTGTCBCCTCGCTGGG-3' (FRAG. NO:1970) (SEQ. ID NO:1983) 5'-GCGBGGCTGTCBCCTCGCTGG-3- (FRAG. NO:1971) (SEQ. ID NO:1984) 5-GCGBGGCTGTCBCCTCGCTG-3' (FRAG. NO:1972) (SEQ. ID NO:1985) 5'-GCGBGGCTGTCBCCTCGCT-3 (FRAG. NO: 1973) (SEQ. ID NO: 1986) 5'-GCGBGGCTGTCBCCTCGC-3 (FRAG. NO:1974) (SEQ. ID NO:1987) 5'-GCGBGGCTGTCBCCTCG-3 (FRAG. NO:1975) (SEQ. ID NO:1988) 5'-GCGBGGCTGTCBCCTC-3 (FRAG. NO:1976) (SEQ. ID NO:1989) 5'-GCGBGGCTGTCBCCT-3 (FRAG. NO:1977) (SEQ. ID NO:1990) 5'-GCGBGGCTGTCBCC-3' (FRAG. NO: 1978) (SEQ. ID NO: 1991) 5'-GCGBGGCTGTCBC-3' (FRAG. NO:1979) (SEQ. ID NO:1992) 5'-GCGBGGCTGTCB-3' (FRAG. NO:1980) (SEQ. ID NO:1993) 5'-GCGBGGCTGTC-3 (FRAC. NO:1981) (SEQ. ID NO:1994) 5'-GCGBGGCTGT-3' (FRAG. NO:1982) (SEQ. ID NO:1995) 5'-CGBGGCTGTCBCCTCGCTGGGCCC-3'(FRAG. NO:1983) (SEQ. ID NO:1996) 5'-GBGGCTGTCBCCTCGCTGGGCCC-3- (FRAG. NO:1984) (SEQ. ID NO:1997) 5'-BGGCTGTCBCCTCGCTGGGCCC-3- (FRAG. NO:1985) (SEQ. ID NO:1998) 5'-GGCTGTCBCCTCGCTGGGCCC-3 (FRAG. NO:1986) (SEQ. ID NO:1999) 5Y-GCTGTCBCCTCGCTGGGCCC-3- (FRAG. NO:1987) (SEQ. ID NO:2000) 5'-CTGTCBCCTCGCTGGGCCC-3' (FRAG. NO:1988) (SEQ. ID NO:2001) 5'-TGTCBCCTCGCTGGGCCC-3' (FRAG. NO:1989) (SEQ. ID NO:.2002) 5'-GTCBCCTCGCTGGGCCC-3' (FRAG. NO:1990) (SEQ. ID NO:2003) 5'-TCBCCTCGCTGGGCCC-3' (FRAG. NO:1991) (SEQ. ID NO:2004) 5'-CBCCTCGCTGGGCCC-3 (FRAG. NO: 1992) (SEQ. ID NO:2005) 5'-BCCTCGCTGGGCCC-3' (FRAG. NO:1993) (SEQ. ID NO:2006) 5'-CCTCGCTGGGCCC-3 (FRAG. NO:1994) (SEQ. ID NO:2007) 5'-CTCGCTGGGCCC-3 (FRAG. NO:1995) (SEQ. ID NO:2008) 5'-TCGCTGGGCCC-3' (FRAG. NO:1996) (SEQ. ID NO:2009) 5'-CGCTGGGCCC-3' (FRAG. NO:1997) (SEQ. ID NO:2010) 5'-GCGCGGCCGTCBTGGCGGCGTCGGGCCGGGC-3 (FRAG. NO:1998) (SEQ. ID NO:2011) 5'-GCGCGGCCGTCBTGGCGGCGTCGGGCCGGG-3 (FRAG. NO:1999) (SEQ. ID NO:2012) 5'-GCGCGGCCGTCBTGGCGGCGTCGGGCCGG-3 (FRAG. NO:2000) (SEQ. ID NO:2013) 5'-CGCGCCTCBGGCGCGCGGCC-3'FRA. N:201)(SEQ. IDNO:2014) 0 35 5'-GCGCGGCCGTCBTGGCGGCGTCGGGCC-3' (FRAG. NO:200) (SQ 5'GGGCGCTGGCTGG-'FA.N:03 (SEQ. ID NO:201) 5'-GGCGCCGTBTGCGGGTCGG-3 (FAG. O:204)(SEQ. ID NO:201) 5'-GCGCGGCCGTCBTGGCGGCGTCGG-3 (FRAG. NO:200) (SEQ. ID NO:201) 5'-GCGCGGCCGTCBTGGCGGCGTCG-3 (FRAG. NO:200) (SEQ. ID NO:201) 5'-GCGCGGCCGTCBTGGCGGCGTC-3 (FRAG. NO:200) (SEQ. ID NO:201) 40 5'-GCGCGGCCGTCBTGGCGGCGT-3' (FRAG. NO:200) (SEQ. ID NO:202) :'GGGCGCBGCGG3 (FA.N:09 SQ:DN:02 5'-GCGCGGCCGTCBTGGCGGC-3- (FRAG. NO:2010) (SEQ. ID NO:2023) 5'-GCGCGGCCGTCBTGGCGG-3 (FRAG. NO:201 1) (SEQ. ID NO:2024) 5'-GCGCGGCCGTCBTGGCG-3 (FRAG. NO:2012) (SEQ. ID NO:2025) 5'-GCGCGGCCGTCBTGGC-3' (FRAG. NO:2013) (SEQ. ID NO:2026) 5'-GCGCGGCCGTCBTGG-3 (FRAG. NO:2014) (SEQ. ID NO:2027) 5'-GCGCGGCCGTCBTG-3 (FRAG. NO:2015) (SEQ. ID NO:2028) 5'-GCGCGGCCGTCBT-3' (FRAG. NO:2016) (SEQ. ID NO:2029) V o 50 5'-GCGCGGCCGTCB-3 (FRAG. NO:2017) (SEQ. ID NO:2030) '00. 5'-GCGCGGCCGTC-3' (FRAG. NO:2018) (SEQ. ID NO:2031) 5'-GCGCGGCCGT-3- (FRAG. NO:20 19) (SEQ. ID NO:2032) 5'-CGCGGCCGTCBTGGCGGCGTCGGGCCGGGC-3' (FRAG. NO:2020) (SEQ. ID NO:2033) 5*GGCGCTGGCTGGCGC3(RG DN:04 5'-CGGCCGTCBTGGCGGCGTCGGGCCGGGC-3 (FRAG. NO:202) (SEQ. ID NO:203) 55 5'-GGCCGTCBTGGCGGCGTCGGGCCGGGC-3 (FRAG. NO:202) (SEQ. ID NO:203) 5'-GCCGTCBTGGCGGCGTCGGGCCGGGC-3 (FRAG. NO:202) (SEQ. ID NO:203) 5'-CCGTCBTGGCGGCGTCGGGCCGGGC-3 (FRAG. NO:202) (SEQ. ID NO:203) 5'-CGTCBTGGCGGCGTCGGGCCGGGC-3 (FRAG. NO:202) (SEQ. ID NO203) -GCTGGCTGGCGG-'(RG O226 SQ DN:09 3D dnv H:\Gabriela\Keep\Spc~i\93951-98.doc 05/07/02 68 5'-GTCBTGGCGGCGTCGGGCCGGGC-3- (FRAG. NO:2027) (SEQ. ID NO:2040) 5'-TCBTGGCGGCGTCGGGCCGGGC-3- (FRAG. NO:2028) (SEQ. ID NO:2041) 5'-CBTGGCGGCGTCGGGCCGGGC-3- (FRAG. NO:2029) (SEQ. ID NO:2042) 5'-BTGGCGGCGTCGGGCCGGGC-3 (FRAG. NO:2030) (SEQ. ID NO:2043) 5'-TGGCGGCGTCGGGCCGGGC-3 (FRAG. NO:2031) (SEQ. ID NO:2044) 5'-GGCGGCGTCGGGCCGGGC-3 (FRAG. NO:2032) (SEQ. ID NO:2045) 5'-GCGGCGTCGGGCCGGGC-3 (FRAG. NO:2033) (SEQ. ID NO:2046) 5'-CGGCGTCGGGCCGGGC-3' (FRAG. NO:2034) (SEQ. ID NO:2047) 5'-GGCGTCGGGCCGGGC-3 (FRAG. NO:2035) (SEQ. ID NO:2048) 5'-GCGTCGGGCCGGGC-3 (FRAG. NO:2036) (SEQ. ID NO:2049) 5'-CGTCGGGCCGGGC-3' (FRAG. NO:2037) (SEQ. ID NO:2050) 5'-GTCGGGCCGGGC-3'(FRAG. NO:2038) (SEQ. ID NO:2051) 5'-TCGGGCCGGGC-3 (FRAG. NO:2039) (SEQ. ID NO:2052) 5'-CGGGCCGGGC-3' (FRAG. NO:2040) (SEQ. ID NO:2053) 5'-CCGCBGGCCBGGGCGCGCCGCCGGCCGGGCCG-3 (FRAG. NO:2041) (SEQ. ID NO:2054) 5.-CCGCBGGCCBGGGCGCGCCGCCGGCCGGGCC-3'(FRAG. NO:2042) (SEQ. ID NO:2055) 5'-CCGCBGGCCBGGGCGCGCCGCCGGCCGGGC-3' (FRAG. NO:2043) (SEQ. ID NO:2056) 5'-CCGCBGGCCBGGGCGCGCCGCCGGCCGGG-3' (FRAG. NO:2044) (SEQ. ID NO:2057) 5'-CCGCBGGCCBGGGCGCGCCGCCGGCCGG-3 (FRAG. NO:2045) (SEQ. ID NO:2058) 5'-CCGCBGGCCBGGGCGCGCCGCCGGCCG-3' (FRAG. NO:2046) (SEQ. ID NO:2059) 5'-CCGCBGGCCBGGGCGCGCCGCCGGCC-3 (FRAG. NO:2047) (SEQ. ID NO:2060) 5'-CCGCBGGCCBGGGCGCGCCGCCGGC-3- (FRAG. NO:2048) (SEQ. ID NO:2061) 5'-CCGCBGGCCBGGGCGCGCCGCCGG-3- (FRAG. NO:2049) (SEQ. ID NO:2062) 5'-CCGCBGGCCBGGGCGCGCCGCCG..3 (FRAG. NO:2050) (SEQ. ID NO: 2063) 5'-CCGCBGGCCBGGGCGCGCCGCC-3- (FRAG. NO:2051) (SEQ. ID NO:2064) 5'-CCGCBGGCCBGGGCGCGCCGC-3- (FRAG. NO:2052) (SEQ. ID NO:2065) 5'-CCGCBGGCCBGGGCGCGCCG-3 (FRAG. NO:2053) (SEQ. ID NO:2066) 5'-CCGCBGGCCBGGGCGCGCC-3' (FRAG. NO:2054) (SEQ. ID NO:2067) 5'-CCGCBGGCCBGGGCGCGC-3 (FRAG. NO:2055) (SEQ. ID NO:2068) 5'-CCGCBGGCCBGGGCGCG-3'(FRAG. NO:2056) (SEQ. ID NO:2069) 5'-CCGCBGGCCBGGGCGC-3 (FRAG. NO:2057) (SEQ. ID NO:2070) 5'-CCGCBGGCCBGGGCG-3' (FRAG. NO:2058) (SEQ. ID NO:2071) 5'-CCGCBGGCCBGGGC-3' (FRAG. NO:2059) (SEQ. ID NO:2072) 5'-CCGCBGGCCBGGG-3 (FRAG. NO:2060) (SEQ. ID NO:2073) 5-CCGCBGGCCBGG-3 (FRAG. NO:2061) (SEQ. ID NO:2074) 5'-CCGCBGGCCBG-3 (FRAG. NO:2062) (SEQ. ID NO:2075) 5'-CCGCBGGCCB-3- (FRAG. NO:2063) (SEQ. ID NO:2076) *5'-CCGCBGGCC-3'(FRAG. NO:2064) (SEQ. ID NO:2077) 5'-CGCBGGCCBGGGCGCGCCGCCGGCCGGGCCG-3 (FRAG. NO:2065) (SEQ. ID NO:2078) 5'-GCBGGCCBGGGCGCGCCGCCGGCCGGGCCG-3 (FRAG. NO:2066) (SEQ. ID NO:2079) 5'-CBGGCCBGGGCGCGCCGCCGGCCGGGCCG-3' (FRAG. NO:2067) (SEQ. ID NO:2080) *5'-BGGCCBGGGCGCGCCGCCGGCCGGGCCG-3 (FRAG. NO:2068) (SEQ. ID NO:2081) 5'-GGCCBGGGCGCGCCGCCGGCCGGGCCG-3' (FRAG. NO:2069) (SEQ. ID NO:2082) 5'-GCCBGGGCGCGCCGCCGGCCGGGCCG-3 (FRAG. NO:2070) (SEQ. ID NO:2083) 5'-CCBGGGCGCGCCGCCGGCCGGGCCG-3 (FRAG. NO:2071) (SEQ. ID NO:2084) *5'-CBGGGCGCGCCGCCGGCCGGGCCG-3- (FRAG. NO:2072) (SEQ. ID NO:2085) *.5'-BGGGCGCGCCGCCGGCCGGGCCG-3- (FRAG. NO:2073) (SEQ. ID NO:2086) 5'-GGGCGCGCCGCCGGCCGGGCCG-3 (FRAG. NO:2074) (SEQ. ID NO:2087) 5'-GGCGCGCCGCCGGCCGGGCCG-3'(FRAG. NO:2075) (SEQ. ID NO:2088) 5'-GCGCGCCGCCGGCCGGGCCG-3' (FRAG. NO:2076) (SEQ. ID NO:2089) 5'-CGCGCCGCCGGCCGGGCCG-3 (FRAG. NO:2077) (SEQ. ID NO:2090) 5-GCGCCGCCGGCCGGGCCG-3' (FRAG. NO:2078) (SEQ. ID NO:2091) 5'-CGCCGCCGGCCGGGCCG-3 (FRAG. NO:2079) (SEQ. ID NO:2092) 5'-GCCGCCGGCCGGGCCG-3' (FRAG. NO:2080) (SEQ. ID NO:2093) 5'-CCGCCGGCCGGGCCG-3 (FRAG. NO:2081) (SEQ. ID NO:2094) *5-CGCCGGCCGGGCCG-3 (FRAG. NO:2082) (SEQ. ID NO:2095) 5'-GCCGGCCGGGCCG-3' (FRAG. NO:2083) (SEQ. ID NO:2096) 5'-CCGGCCGGGCCG-3 (FRAG. NO:2084) (SEQ. ID NO:2097) 5'-CGGCCGGGCCG-3 (FRAG. NO:2085) (SEQ. ID NO:2098) 5'-GGCCGGGCCG-3 (FRAG. NO:2086) (SEQ. ID NO:2099) H:\Gabriela\Keep\Spcdt\9395 -98.doc 05/07/02 69 5'-GGGCGC8GGCTCCGCB-3 (FRAG. NO:2087) (SEQ. I D NO:21 00) 5'-GGGCCCCTGGCTCGGCCCCGCGGCCCGGCTTGCCCGCCCGGCCCGG-3' (FRAG. NO:2088) (SEQ. ID NO:2101) 5'-GGGCCCCTGGCTCGGCCCCGCGGCCCGGCTrGCCCGCCCGGCCCG-3 (FRAG. NO:2089) (SEQ. ID NO:2102) 5'-GGGCCCCTGGCTCGGCCCCGCGGCCCGGCT'FGCCCGCCCGGCCC-3' (FRAG. NO:2090) (SEQ. ID NO:2103) 5'-GGGCCCCTGGCTCGGCCCCGCGGCCCGGC'rrGCCCGCCCGGCC-3- (FRAG. NO:2091) (SEQ. ID NO:2104) 5'-GGGCCCCTGGCTCGGCCCCGCGGCCCGGCT-FGCCCGCCCGGC-3' (FRAG. NO:2092) (SEQ. ID NO:2105) 5'-GGGCCCCTGGCTCGGCCCCGCGGCCCGGCTUGCCCGCCCGG-3 (FRAG. NO:2093) (SEQ. ID NO:2106) 5'-%GGCCCCTGGCTCGGCCCCGCGGCCCGGCTTGCCCGCCCG-3- (FRAG. NO:2094) (SEQ. ID NO:2107) 5'-GGGCCCCTGGCTCGGCCCCGCGGCCCGGCTrGCCCGCCC-3- (FRAG. NO:2095) (SEQ. ID NO:2108) 5'-GGGCCCCTGGCTCGGCCCCGCGGCCCGGCTTGCCCGCC-3' (FRAG. NO:2096) (SEQ. ID NO:2109) 5'-GGGCCCCTGGCTCGGCCCCGCGGCCCGGC-1FGCCCGC-3- (FRAG. NO:2097) (SEQ. ID NO:21 5'-GGGCCCCTGGCTCGGCCCCGCGGCCCGGCTfrGCCCG-3' (FRAG. NO:2098) (SEQ. ID NO:21 11) 5'-GGGCCCCTGGCTCGGCCCCGCGGCCCGGCTrGCCC-3 (FRAG. NO:2099) (SEQ. ID NO:21 12) 5'-GGGCCCCTGGCTCGGCCCCGCGGCCCGGC'rrGCC-3 (FRAG. NO:2100) (SEQ. ID NO:2113) 5'-GGGCCCCTGGCTCGGCCCCGCGGCCCGGCTrGC-3 (FRAG. NO:2101) (SEQ. ID NO:21 14) 5'-GGGCCCCTGGCTCGGCCCCGCGGCCCGGCT-rG-3 (FRAG. NO:2102) (SEQ. ID NO:21 5'-GGGCCCCTGGCTCGGCCCCGCGGCCCGGCTr-3 (FRAG. NO:2103) (SEQ. ID NO:21 16) 5'-GGGCCCCTGGCTCGGCCCCGCGGCCCGGCT-3' (FRAG. NO:2104) (SEQ. ID NO:21 17) 5'-GGGCCCCTGGCTCGGCCCCGCGGCCCGGC-3 (FRAG. NO:2105) (SEQ. ID NO:21 18) 5'-GGGCCCCTGGCTCGGCCCCGCGGCCCGG-3 (FRAG. NO:2106) (SEQ. ID NO:21 19) 5'-GGGCCGCTGGCTCGGCCCCGCGGCCCG-3' (FRAG. NO:2107) (SEQ. ID NO:2120) 5'-GGGCCCCTGGCTCGGCCCCGCGGCCC-3 (FRAG. NO:2108) (SEQ. ID NO:2121) 5'-GGGCCCCTGGCTCGGCCCCGCGGCC-3- (FRAG. NO:2109) (SEQ. ID NO:2122) 5'-GGGCCCCTGGCTCGGCCCCGCGGC-3 (FRAG. NO:21 10) (SEQ. ID NO:2123) 5'-GGGCCCCTGGCTCGGCCCCGCGG-3' (FRAG. NO:2111) (SEQ. ID NO:2124) 5'-GGGCCCCTGGCTCGGCCCCGCG-3 (FRAG. NO:21 12) (SEQ. ID NO:21 5'-GGGCCCCTGGCTCGGCCCCGC-3' (FRAG. NO:2113) (SEQ. ID NO:2126) 5'-GGGCCCCTGGCTCGGCCCCG-3' (FRAG. NO:2114) (SEQ. ID NO:2127) 5'-GGGCCCCTGGCTCGGCCCC-3' (FRAG. NO:2115) (SEQ. ID NO:2128) 5'-GGGCCCCTGGCTCGGCCC-3 (FRAG. NO:2116) (SEQ. ID NO:2129) 5'-GGGCCCCTGGCTCGGCC-3 (FRAG. NO:2117) (SEQ. ID NO:2130) 5'-GGGCCCCTGGCTCGGC-3 (FRAG. NO:2118) (SEQ. ID NO:2131) 5'-GGGCCCCTGGCTCGG-3 (FRAG. NO:2119) (SEQ. ID NO:2132) 5'-GGGCCCCTGGCTCG-3 (FRAG. NO:2120) (SEQ. ID NO:2133) 5'-GGGCCCCTGGCTC-3' (FRAG. NO:2121) (SEQ. ID NO:2134) 5'-GGGCCCCTGGCT-3' (FRAG. NO:2122) (SEQ. ID NO:2135) 5:GCCTGTGCCGGCCG~GCGCGCCG3(RG NO22)(E.I NO:2 136) 5'-CCCCTGGCTCGGCCCCGCGGCCCGGCTGCCCGCCCGGCCCGG-3 (FRAG. NO:212) (SEQ. ID NO:213) 40 5'-CCCCTGGCTCGGCCCCGCGGCCCGGCTGCCCGCCCGGCCGG-3' (FRAG. NO:212) (SEQ. ID NO:213) 5'-CCCTGGCTCGGCCCCGCGGCCCGGCUGCCCGCCCGGCCCGG-3 (FRAG. NO:212) (SEQ. ID NO:2130) 5-CTGGCTCGGCCCCGCGGCCCGGC~rGCCCGCCCGGCCCGG-3- (FRAG. NO:212)(SQ ID 5'-TGGCTCGGCCCCGCGGCCCGGCT-GCCCGCCCGGCCCGG-3 (FRAG. NO:212) (SEQ. ID NO:214) 5!-GGCTCGGCCCCGCGGCCCGGCT7GCCCGCCCGGCCCGG-3- (FRAG. NO:212) (SEQ. ID NO:214) 5'-GCTCGGCCCCGCGGCCCGGCl7GCCCGCCCGGCCCGG-3'(FRAG NO:213) (SEQ. ID NO:214) 5'-CTCGGCCCCGCGGCCCGGCTGCCCGCCCGGCCCGG-3- (FRAG. NO:213) (SEQ. ID NO:214) 5-TCGGCCCCGCGGCCCGGCTTGCCCGCCCGGCCCGG-3'(FRAG. NO:213) (SEQ. ID NO:214) 5'-CGGCCCCGCGGCCCGGCTGCCCGCCCGGCCCGG-3- (FRAG. NO:213) (SEQ. ID NO:214) so. 0. 5'-CGCCCCGCGGCCCGGCTrGCCCGCCCGGCCCGG-3 (FRAG. NO:213) (SEQ. ID NO:214) 50 5'-GCCCCGCGGCCCGGCTGCCCGCCCGGCCCGG-3 (FRA. NO:213) (SEQ. ID NO: 214) 50 5'-CCCCGCGGCCCGGCTGCCCGCCCGGCCCGG-3' (FRAG. NO:213) (SEQ. ID NO: 214) *00 5'-CCCGCGGCCCGGCTGCCCGCCCGGCCCGG-3 (FRAG. NO:213) (SEQ. ID NO:215) *so..*5'-CCGCGGCCCGGCTGCCCGCCCGGCCCGG-3'(FRAG. NO:213) (SEQ. ID NO:215) 5'-CGCGGCCCGGCTGCCCGCCCGGCCCGG-3 (FRAG. NO:210) (SEQ. ID NO:215) 555'-GCGGCCCGGCJ7GCCCGCCCGGCCCGG-3 (FRAG. NO:214) (SEQ. ID NO:215) 5'-CGGCCCGGCTGCCCGCCCGGCCCGG-3 (FRAG. NO:214) (SEQ. ID NO:215) 5'-GGCCCGGCT7GCCCGCCCGGCCCGG-3- (FRAG. NO:214) (SEQ. ID NO:215) 5'-GCCCGGCTfGCCCGCCCGGCCCGG-3 (FRAG. NO:214) (SEQ. ID NO:215) 5'-CCCGGCTTGCCCGCCCGGCCCGG-3' (FRAG. NO:214) (SEQ. ID NO:215) H:\Gabriela\Keep\Speci\939S I-98.doc 05/07/02 5'-CCGGC~rGCCCGCCCGGCCCGG-3 (FRAG. NO:2146) (SEQ. ID NO:2159) 5'-CGGCTTGCCCGCCCGGCCCGG-3- (FRAG. NO:2147) (SEQ. ID NO:21 -GGCT-rGCCCGCCCGGCCCGG-3' (FRAG. NO:2148) (SEQ. ID NO:2161) 5'-GCT-GCCCGCCCGGCCCGG-3 (FRAG. NO:2149) (SEQ. ID NO:2162) 5'-CTI7GCCCGCCCGGCCCGG-3' (FRAG. NO:2150) (SEQ. ID NO:2163) 5'-TrGCCCGCCCGGCCCGG-3 (FRAG. NO:2151) (SEQ. ID NO:2164) 5'-TGCCCGCCCGGCCCGG-3 (FRAG. NO:2152) (SEQ. ID NO:2165) 5'-GCCCGCCCGGCCCGG-3 (FRAG. NO:2153) (SEQ. ID NO:2166) 5'-CCCGCCCGGCCCGG-3 (FRAG. NO:2154) (SEQ. ID NO:2167) 5'-CCGCCCGGCCCGG-3 (FRAG. NO:2155) (SEQ. ID NO:2168) 5'-CGCCCGGCCCGG-3 (FRAG. NO:2156) (SEQ. ID NO:2169) 5'-GCCCGGCCCGG-3 (FRAG. NO:2157) (SEQ. ID NO:2170) 5'-GGCGGGGGCGGCGGCGCCTGGCTCGCCTBGGGCCCC-3- (FRAG. NO:2158) (SEQ. ID NO:21 71) GCCTGGCTCGCCTBGGGCCC-3- (FRAG. NO:2159) (SEQ. ID NO:2172) 5'-GGCGGGGGCGGCGGCGCCTGGCTCGCCTBGGGCC-3' (FRAG. NO:2160) (SEQ. ID NO:2173) -GGCGGGGGCGGCGGCGCCTGGCTCGCCTBGGGC-3' (FRAG. NO:2161) (SEQ. ID NO:2174) 5'-GGCGGGGGCGGCGGCGCCTGGCTCGCCTBGGG-3' (FRAG. NO:2162) (SEQ. ID NO:2175) 5'-GGCGGGGGCGGCGGCGCCTGGCTCGCCTBGG-3 (FRAG. NO:2163) (SEQ. ID NO:2176) 5'-GGCGGGGGCGGCGGCGCCTGGCTCGCCTBG-3' (FRAG. NO:2I64) (SEQ. ID NO:2177) 5'-GGCGGGGGCGGCGGCGCCTGGCTCGCCTB-3 (FRAG. NO:2165) (SEQ. ID NO:2178) 5'-GGCGGGGGCGGCGGCGCCTGGCTCGCCT-3 (FRAG. NO:2166) (SEQ. ID NO:2179) 5'-GGCGGGGGCGGCGGCGCCTGGCTCGCC-3- (FRAG. NO:2167) (SEQ. ID NO:2180) 5'-GGCGGGGGCGGCGGCGCCTGGCTCGC-3- (FRAG. NO:2168) (SEQ. ID NO:2181) 5'-GGCGGGGGCGGCGGCGCCTGGCTCG-3 (FRAG. NO:2169) (SEQ. ID NO:2182) 5'-GGCGGGGGCGGCGGCGCCTGGCTC-3- (FRAG. NO:2170) (SEQ. ID NO:2183) 5'-GGCGGGGGCGGCGGCGCCTGGCT-3- (FRAG. NO:2171) (SEQ. ID NO:2184) 5'-GGCGGGGGCGGCGGCGCCTGGC-3' (FRAG. NO:21 72) (SEQ. ID NO:2185) 5'-GGCGGGGGCGGCGGCGCCTGG-3 (FRAG. NO:21 73) (SEQ. ID NO:21 86) 5'-GGCGGGGGCGGCGGCGCCTG-3- (FRAG. NO:2 174) (SEQ. ID NO:21 87) 5'-GGCGGGGGCGGCGGCGCCT-3' (FRAG. NO:2175) (SEQ. ID NO:2188) 5'-GGCGGGGGCGGCGGCGCC-3 (FRAG. NO:2176) (SEQ. ID NO:2189) 5'-GGCGGGGGCGGCGGCGC-3 (FRAG. NO:2177) (SEQ. ID NO:2190) 5'-GGCGGGGGCGGCGGCG-3' (FRAG. NO:2178) (SEQ. ID NO:2191) 5'-GGCGGGGGCGGCGGC-3 (FRAG. NO:2179) (SEQ. ID NO:2192) 5'-GGCGGGGGCGGCGG-3 (FRAG. NO:2180) (SEQ. ID NO:2193) 0 5'-GGCGGGGGCGGCG-3 (FRAG. NO:2181) (SEQ. ID NO:2194) 5'-GGCGGGGGCGGC-3 (FRAG. NO:2182) (SEQ. ID NO:2 195) 00 5'-GGCGGGGGCGG-3 (FRAG. NO:2183) (SEQ. ID NO:2196) 5'-GCGGGGGCGGCGGCGCCTGGCTCGCCTBGGGCCCC-3- (FRAG. NO:2184) (SEQ. ID NO:2197) 5'-CGGGGGCGGCGGCGCCTGGCTCGCCTBGGGCCCC-3 (FRAG. NO:2185) (SEQ. ID NO:2198) 5'-GGGGGCGGCGGCGCCTGGCTCGCCTBGGGCCCC-3' (FRAG. NO:2186) (SEQ. ID NO:2199) 5'-GGGGCGGCGGCGCCTGGCTCGCCTBGGGCCCC-3 (FRAG. NO:2 187) (SEQ. ID NO:2200) 5'-GGGCGGCGGCGCCTGGCTCGCCTBGGGCCCC-3' (FRAG. NO:2188) (SEQ. ID NO:2201) 5'-GGCGGCGGCGCCTGGCTCGCCTBGGGCCCC-3 (FRAG. NO:2189) (SEQ. ID NO:2202) 5'-GCGGCGGCGCCTGGCTCGCCTBGGGCCCC-3 (FRAG. NO:2190) (SEQ. ID NO:2203) *-GCGGCGCCCTGGCC3(RG NO:21 1 (SEQ. ID NO:2204) 5-GGGGCCCTGCTCCCTBGGCCC-3 (FAG. O:292)(SEQ. ID NO:2205) 0 5'-GCGGCGCCTGGCTCGCCTBGGGCCCC-3' (FRAG. NO:2193) (SEQ. ID NO:2206) 5'-CGGCGCCTGGCTCGCCTBGGGCCCC-3' (FRAG. NO:2194) (SEQ. ID NO:2207) :0..50 5.-GGCGCCTGGCTCGCCTBGGGCCCC-3- (FRAG. NO:2195) (SEQ. ID NO:2208) *5'-GCGCCTGGCTCGCCTBGGGCCCC-3' (FRAG. NO:2196) (E.ID N:29 5'CCTGTGCTGGCC3 FRG O29)(SQ DN:20 5'-GCCTGGCTCGCCTBGGGCCCC-3 (FRAG. NO:219) (SEQ. ID NO:221) -CCTGGCTCGCCTBGGGCCCC-3' (FRAG. NO:219) (SEQ. ID NO:221 5-CTGGCTCGCCTBGGGCCCC-3 (FRAG. NO:2I9) (SEQ. ID NO:221) 55 5-TGGCTCGCCTBGGGCCCC3(FRAG. NO:220) (SEQ. ID NO:221) 0000CCTGGCC-'FA. O20)(EQ 5'-TGCTCGCCTBGGGCCCC-3' (FRAG. NO:220) (SEQ. ID NO:221) 5'-GCTCGCCTBGGGCCCC-3(FRAG. NO:220) (SEQ. ID NO:221) H:\Gabriela\KeecpkSpcci\939SI -98.doc 05/07/02 5'-TCGCCTBGGGCCCC-3' (FRAG. NO:2205) (SEQ. ID NO:2218) S-CGCCTBGGGCCCC-3 (FRAG. NO:2206) (SEQ. ID NO:2219) 5'-GCCTBGGGCCCC-3' (FRAG. NO:2207) (SEQ. ID NO:2220) 5'-CCTBGGGCCCC-3 (FRAG. NO:2208) (SEQ. ID NO:2221) 5'-CTBGGGCCCC-3' (FRAG. NO:2209) (SEQ. ID NO:2222) 5'-GGGTGGGCBCGGCGGCC-3'(FRAG. NO:2210) (SEQ. ID NO:2223) 5'-GGTCGGCGBBGBGCTCGTCGTGGC-3 (FRAG. NO:22I I) (SEQ. ID N 0:2224) 5'-GGTCGGCGBBGBGCTCGTCGTGG-3- (FRAG. NO:2212) (SEQ. ID NO:2225) 5'-GGTCGGCGBBGBGCTCGTCGTG-3- (FRAG. NO:2213) (SEQ. I D NO:2226) 5'-GGTCGGCGBBGBGCTCGTCGT-3 (FRAG. NO:2214) (SEQ. ID NO:2227) 5'-GGTCGGCGBBGBGCTCGTCG-3- (FRAG. NO:2215) (SEQ. ID NO:2228) 5'-GGTCGGCGBBGBGCTCGTC-3- (FRAG. NO:2216) (SEQ. ID NO:2229) 5'-GGTCGGCGBBGBGCTCGT-3' (FRAG. NO:2217) (SEQ. ID NO:2230) 5'-GGTCGGCGBBGBGCTCG-3' (FRAG. NO:2218) (SEQ. ID NO:2231) 5'-GGTCGGCGBBGBGCTC-3 (FRAG. NO:2219) (SEQ. ID NO:2232) 5'-GGTCGGCGBBGBGCT-3' (FRAG. NO:2220) (SEQ. ID NO:2233) 5'-GGTCGGCGBBGBGC-3' (FRAG. NO:2221) (SEQ. ID NO:2234) 5'-GGTCGGCGBBGBG-3 (FRAG. NO:2222) (SEQ. ID NO:2235) 5'-GGTCGGCGBBGB-3 (FRAG. NO:2223) (SEQ. ID NO:2236) 5'-GGTCGGCGBBG-3' (FRAG. NO:2224) (SEQ. ID NO:2237) 5'-GTCGGCGBBGBGCTCGTCGTGGC-3' (FRAG. NO:2225) (SEQ. ID NO:2238) 5'-TCGGCGBBGBGCTCGTCGTGGC-3- (FRAG. NO:2226) (SEQ. ID NO:2239) 5'-CGGCGBBGBGCTCGTCGTGGC-3- (FRAG. NO:2227) (SEQ. ID NO:2240) 5'-GGCGBBGBGCTCGTCGTGGC-3' (FRAG. NO:2228) (SEQ. ID NO:2241) 5'-GCGBBGBGCTCGTCGTGGC-3 (FRAG. NO:2229) (SEQ. ID NO:2242) 5'-CGBBGBGCTCGTCGTGGC-3 (FRAG. NO:2230) (SEQ. ID NO:2243) 5'-GBBGBGCTCGTCGTGGC-3'(FRAG. NO:2231) (SEQ. ID NO:2244) 5-BBGBGCTCGTCGTGGC-3 (FRAG. NO:2232) (SEQ. ID NO:2245) 5'-BGBGCTCGTCGTGGC-3 (FRAG. NO:2233) (SEQ. ID NO:2246) 5'-GBGCTCGTCGTGGC-3 (FRAG. NO:2234) (SEQ. ID NO:2247) 5'-BGCTCGTCGTGGC-3 (FRAG. NO:2235) (SEQ. ID NO:2248) 5'-GCTCGTCGTGGC-3' (FRAG. NO:2236) (SEQ. ID NO:2249) 5'-CTCGTCGTGGC-3' (FRAG. NO:2237) (SEQ. ID NO:2250) ***5'-TCGTCGTGGC-3 (FRAG. NO:2238) (SEQ. ID NO:2251) 35 Y-GGGGCCCCGCGCCGCCCGCC-3' (FRAG. NO:2239) (SEQ. ID NO:2252) 5-GGCCCCGCCC3:RG NO220 (SEQ. ID NO:2253) O:241)(SEQ. ID NO:2254) :5'-GGGGCCCCGCGCCGCCC-3' (FRAG. NO:2242) (SEQ. ID NO:2255) 40 5'-GGGGCCCCGCGCCGCC-3' (FRAG. NO:2243) (SEQ. ID NO:2256) 40 5'-GGGGCCCCGCGCCGC-3 (FRAG. NO:2244) (SEQ. ID NO:2257) 5'-GGGGCCCCGCGCCG-3 (FRAG. NO:2245) (SEQ. ID NO:2258) :5'-GGGGCCCCGCGCC-3 (FRAG. NO:2246) (SEQ. ID NO:2259) 5'-GGGGCCCCGCGC-3 (FRAG. NO:2247) (SEQ. ID NO:2260) 5'-GGGCCCCGCGCCGCCCGCC-3 (FRAG. NO:2248) (SEQ. ID NO:2261) 5'-GGCCCCGCGCCGCCCGCC-3' (FRAG. NO:2249) (SEQ. ID NO:2262) 5'-GCCCCGCGCCGCCCGCC-3'(FRAG. NO:2250) (SEQ. ID NO:2263) 5'-CCCCGCGCCGCCCGCC-3 (FRAG. NO:2251) (SEQ. ID NO:2264) 5-CCCGCGCCGCCCGCC-3 (FRAG. NO:2252) (SEQ. ID NO:2265) 5-CCGCGCCGCCCGCC-3 (FRAG. NO:2253) (SEQ. ID NO:2266) 5'-CGCGCCGCCCGCC-3 (FRAG. NO:2254) (SEQ. ID NO:2267) 5'-GCGCCGCCCGCC-3' (FRAG. NO:2255) (SEQ. ID NO:2268) 5'-CGCCGCCCGCC-3 (FRAG. NO:2256) (SEQ. ID NO:2269) 5'-GCCGCCCGCC-3- (FRAG. NO:2257) (SEQ. ID NO:2270) **5'-GGGGCGCGCGGGGCCGCCGGG-3' (FRAG. NO:2258) (SEQ. ID NO:2271) 55 5'-GGCGGGGBGCGGCBGGGCCCGGGCCC-3 (FRAG. NO:2259) (SEQ. ID NO:2272) 5'-GGCGCGTCGCCGTCGCCCCBGTCGGGCTCGCGC-3 (FRAG. NO:2260) (SEQ. ID NO:2273) 5'-GCGCGGGCBBCBGCGBGCCGGGCGCG-3 (FRAG. NO:2261) (SEQ. ID NO:2274) 5'-GCGCBCGGGCCCBCCTGCGCGGGC-3- (FRAG. NO:2262) (SEQ. ID NO:2275) 5'-GGGCGGGGTGGGCTGCCC'fGCGGCCGCC-3' (FRAG. NO:2263) (SEQ. ID NO:2276) H:\Gabriela\Keep\Speci\93951I-98.doc 05/07/02 72 5'-GGGCTGCTGCGCGGCGGCTCCGGCGA-3- (FRAG. NO:2264) (SEQ. ID NO:2277) 5'-CTCCCGGGCGGGGCCGGGCGCGGGG-3'(FRAG. NO:2265) (SEQ. ID NO:2278) 5'-GGGCTGCCGCGGTCCGGGCCCCTCTfGCCGGCG-3 (FRAG. NO:2266) (SEQ. ID NO:2279) 5'-GCGCTCGCGCCGCTGCCGG-3' (FRAG. NO:2267) (SEQ. ID NO:2280) 5'-GCGCCGCTrGGCCTGTCGCGGC-3- (FRAG. NO:2268) (SEQ. ID NO:2281) 5'-GCTGCTCCBCGCGCTGG-3 (FRAG. NO:2269) (SEQ. ID NO:2282) 5'-GCCGGBGGCCGGCCBGGTCCCGCG-3' (FRAG. NO:2270) (SEQ. ID NO:2283) 5'-CCCGGCGGCCGGCBGGBBGGGCGGGCTGGGC-3 (FRAG. NO:2271) (SEQ. ID NO:2284) 5'-GTCTCTCCCGCCCCGGCCGCGCG-3- (FRAG. NO:2272) (SEQ. ID NO:2285) 5'-GGGCGTCCGCTCCGGGCCGTCGGG-3' (FRAG. NO:2273) (SEQ. ID NO:2286) 5'-GCGGGCACGCGGCGGCTCTGGCGTCGGC-3' (FRAG. NO:2274) (SEQ. ID NO:2287) Where B is adenosine, or, more preferbly, replaces adenosine and is a universal base, and adenosine A2a receptor agonist, an adenosine A2b receptor antagonist, an adenosine A3 receptor antagonist, or an adenosine Al receptor antagonist.

Bradykinin Receptor Anti-sense Oligonucleotide Fragments BGCBTGTCGG CGCGGTCCCG 'TBBGBGTGG GCCCGCCAGC CCAGCCACTC CACT~rGGGGG CGGGTGGCCA GCACGAACAG CACCCAGAGG AAGGGGGGCG GCGCAGAAGG GCAGCCCGCA GGCCAGGATC AGGTCTGCTG CGGCCGGAGA TAATGGCATT CACCACGCGG GGGCCCAGCG CACGCCGCGC ATCCGGCCCG GGTTCTGACC TGCAGCCCCC GTCTCCT-rGG CATrCCTGGG CCCCAGTCAC TCCTCTCCCT GCCCCCGT-fG CTGGGGCAGG GACGGGGTG BCBTTGBGCB TGTCGGCGCG GTCCCGTTBB GBGTGGGCGC GCCAGCCCAG CCACTCCACT TGGGGGCGGG TGGCCAGCAC GAACAGCACC CAGAGGAAGG GGGGCGGCGC AGAAGGGCAG CCCGCAGGCC AGGATCAGGT CTGCTGCGGC CGGAGATAAT GGCATI'CACC ACGCGGCGGC CCAGCGCACG CCGCGCATCC GGCCCGGGTT CTGACCTGCA GCCCCCGTCT CCTTFGGCA1T CCTGGGCCCC AGTCACTCCT CTCCCTGCCC CCCT7GCTGG GGCAGGGACG GCCGTGTTGT CBGTGGTGCT GCCCGM~GB GGTBTGGCGC TCCBCCBBT-r CCCYTTCTC CTrGTTrrCC GTT[CTCT-rG CCGTCTGTGG TT-3 (FRAG. NO:2275) (SEQ. ID NO:2288) 5'-GGTGBCBTTGBGCBTGTCGGCGC-3- (FRAG. NO:2276) (SEQ. ID NO:2289) 5'-GGTCCCG1TBBGBGTGGGCCC-3' (FRAG. NO:2277) (SEQ. ID NO:2290) 5'-GCCAGCCCAGCCACTCCACYITGGGGGC-3' (FRAG. NO:2278) (SEQ. ID NO:2291) 5'-GGGTGGCCAGCACGAACAGCACCCAGAGGAAGGGGGGC-31 (FRAG. NO:2279) (SEQ. ID NO:2292) 5'-GGCCCAGAAGGGCAGCCCGCAGGCCAGGATCAGGTCTGCTGCGGCC-3' (FRAG. NO:2280) (SEQ. ID NO:2293) 5'-GGAGATAATGGCATUCACCACGCGGC-3- (FRAG. NO:2281) (SEQ. ID NO:2294) 5-GGCCCAGCGCACGCCGCGCATCCGGCCC-3' (FRAG. NO:2282) (SEQ. ID NO:2295) 5'-CAGTCCTCTCCCTGCCCCC-3 (FRAG. NO:228) (SEQ. ID NO:229) *5'-GCTCTGGGCAGGCGGG-3 (FRAG. NO:2284) (SEQ. ID NO:229) 35 5'-CGTTGCFCTGTCGCGCGC-3' (FRAG. NO:2287) (SEQ. ID NO:2300) 5'-GGTCCGrBTGGGCC-3' (FRAG. NO:228) (SEQ. ID NO:230) 5'-GCCGCCCAGCACTCCGGGC-3 (FRAG. NO:2289) (SEQ. ID NO:230 40 5'-GGTGCCGCACBGAACGCCCC FAGGAGGGG- (FRA. NO2) (SEQ. ID NO:2303) (FAGGTTCGGC- (FRAG.9 (SEQ.91 (SEQ ID NO:23 5'-GGGTAATGAGCACACACACCCGGGGGC-3 (FRAG.NO29)(E.D NO:230)(SQIDN:3 5'-GGCCCAGCGCAGCCCGCACGGCCC-3 (FAG.TTCGCGC3 NO:2293O22) (SEQ. ID NO:230 (FRAG. NO:229 (SEQ. ID NO:230 ~5'-GTCTCCAGACCGCAT GGCCC-3 (FRAG. NO:229 (SEQ. ID NO:230 5'-CAGTCCTCCTCCCGCCCCC-3 (FRAG. NO:229) (SEQ. ID NO:230) 5'-GCTCTGGCAGGGCGGG.3 (FRAG. NO:229) (SEQ. ID NO:2308) 5'-CCGTGATCTCTGGTGCG-3 (FRAG. NO:229) (SEQ. ID NO:23) 5'-CCCGTTrrGBGGTBTGGC-3' (FRAG. NO:2299) (SEQ. ID NO:1928) 5'-GCTCCBCCBBrCCCTrrrCTCC-3' (FRAG. NO:2300) (SEQ. ID NO:1929) 5'-TfGTFIMCCG'ITTCTCTTG-3- (FRAG. NO:2301) (SEQ. ID NO:1930) S5'-CCGTCTGTGGTT7-3' (FRAG. NO:2302) (SEQ. ID NO:1931) In one preferred embodiment, the links between neighboring mononucleotides are ~iI§fl\IH:\Gabuiela\Kcep\Spcc093951-98.doc 05/07/02 73 phosphodiester links. In another preferred, at least one mononucleotide phosphodiester residue of the antisense oligonucleotide(s) is substituted by a methylphosphonate, phosphotriester, phosphorothioate, phosphorodithioate, boranophosphate, formacetal, thioformacetal, thioether, carbonate, carbamate, sulfate, sulfonate, sulfamate, sulfonamide, sulfone, sulfite, sulfoxide, sulfide, hydroxylamine, 2'-O-methyl, methylene(methyimino), methyleneoxy (methylimino), phosphoramidate residues, and combinations thereof.

The MTA oligos having one or more phosphodiester residues substituted by one or more of the other residues are generally longer lasting, given that these residues are more resistant to hydrolysis than the phosphodiester residue. In some cases up to about 10%, about 30%, about 50%, about 75%, and even all phosphodiester residues may be substituted Typically, the multiple target anti-sense oligonucleotide (MTA oligo) of the invention comprises at least about 7 mononucleotides, in some instances up to 60 and more mononucleotides, preferably about 10 to about 36, and more preferably about 12 to about 21 mononucleotides. However, other lengths are also suitable depending on the length of the target macromolecule. Examples of the MTA oligos of the invention are provided in Table 3 below, which includes ninety-four sequences (SEQ ID NOS.: 2317 through 2411).

Table 3:MTA Oligos, Location Targeted Target MTA Oligo SEQ. ID Location Compound Target No. Targeted

AS

CCC GGC CCC GCC TCG TGC C 2316 5'=1 EPI 2192 CGT CCB TGC CGC GGG CCC 2317 5'=28 (AUG) EPI 2193 GCC CCG CTG CTT GGG CTG CTC TGC CGG G 2318 5'=65 EPI 2194 TCT GTG CTC CTC TCG CCT GGG 2319 5'=137 EPI 2195 TGG TGG GGT GGG TCT TGG TGG 2320 5'=159 EPI 2196 CTG TCC CTG GTC CTG TG 2321 5'=196 EPI 2197 GGT CCC GCT TCT TC 2322 5'=362 EPI 2198 GGG GTT GTT GTT GGT CTG G 2323 5'=401 EPI 2199 TGT CCT CTT TCT GC 2324 5'=656 EPI 2200 30 .*o a H:\Gabriela\KCcp\Spec1i93951-98doc 05/07/02 74 Table 3: MTA Oligos, Location Targeted Target (Cont'd) MTA Oligo SEQ. ID Location Compound Target No. Targeted GCC TCG GGC CTC CC GGC TGG GGT CTG CGT GGC CGG GGG TCG GTG GGT CCG CTG GGG CTG GGG TGC TGG CTT GGG GGG GCT GGG GCC TGG GCC GCC TGG GTG GGC TTG GGG GC GCT GGG TCT GTG CTG TTG CC GTT GTG TGG GGG GCC GCT GGG TCG GGG GGC CTC TGG GCT GTC GCC CCG GGG CCC CC TGG CTC CCC CCT CC GCT CCC CCC TTT CC CGG ACG AAG ACA GAG A GGC TTT GTG GGC TC GCC TGC TCT CCC CC CCC GGC CCC GCC ECG EEC C CCC GGC CCC GCC BCG CCC GGC CCC GCC BCG BBC C CCC GGC CCC GCC ECG CCC GEC CCC GCC TCB EG CCC GEC CCC GCC TC CCG GCC CCG CCT C CCC GEE CCC GCE TEG TGC C CCC GCB TEG TGC C CCC GGE CCC ECC BEG TGC C CBG EEC CCG CCT CGT GCC C CCG CCT CGT GCC CCG GCB CCG CCT CET 0CC CCG GCC CCG CCE CET GCC CCC GEC CCC GEC TCG CCC GGC CEC GEC TCG CCC GGC CCE GCC TEG CCC GGC ECE GEC TCG TEC C CCC GGC CCC GCC ECG 2325 2326 2327 G 2328 2329 2330 2331 2332 2333 2334 2335 2336 2337 2338 2339 2340 2341 2340 2341 2344 2345 2346 2347 2348 2349 2350 2351 2352 2353 2354 2355 2356 2357 2359 2341 2360 2362 2361 2363 2364 2365 2366 2367 2368 2369 2370 5'=697 EPI 2201 5'=769 EPI 2202 5'=953 EPI 2203 5'=1022 EPI 2204 5'=1208 EPI 2205 5'=1272 EPI 2206 5'=1362 EPI 2207 5= 14 51 EPI 2208 5'=1511 EPI 2209 5'=1550 EPI 2210 5'=1772 EPI 2211 5'=1863 EPI 2212 5'=1979 EPI 2213 5'=2011 EPI 2214 5'=2312 EPI 2215 intron EPI 2192-01A HSU50136 intron EPI 2192-01BC4Snhs 5uantr EPI 2192-02A HUMLIPOX 5'untr EPI 2192-02B trans EPI 2192-03A HSNFKBS subunit trans EPI 2192-03B 5'untr EPI 2192-04 TGFI3R1 S'trans EPI 2192-05A HSU58198 Il enhan 5'untr EPI 2192-OSB 3trans EPI 2192-06 HSVECAD intron EPI 2192-07A NFKB2 intron EPI 2192-07B NFKB2 51trans EPI 2192-08 Carboxypep 31trans EPI 2192-09 HUMADRA2C a2adr kidney 5'untrs EPI 2192-10 HUMFK506B 5'untrs EPI 2192-11 HSNBARKS1 ctadr kinase 5'UJTR EPI 2192 -12 HSNFXN1 NFKBl 3'UTR EPI 2192-13 HSILF (transcrp EPI-2192-14 NFKB/C4/ TGFBrec1 MTA EPI-2192 -15 NFKB/C4 Syn /5-LO MTA 3' trans EPI-2193-01 MET Oncoqene 3' trans EPI-2193-02 HSFGR2 (IG) mid cod EPI-2193-03 mid cod EPI-2193-04 MTK14 31trans EPI-2193-05 HIJMTNFR AUG Probl.HUMPTCH cardiacK+channel intr EPI-2195-01 HUMCSPAcY t o t ox intr EPI-2195-02 HSINOSXO8 inducible NOS EPI-2195-03 HUMACHRM2M.usc m2acetylchRec EPI-2195-04 s863 71s 1 Neurokinin3 Rec EPI-2195-05 HUMMIPlAmacro inf lam. factor

S

S. S S

S.

S

555.

CCC GOC CCC GCC ECG 50 T CGCGG TCC BTG CCG CGG OCC TCC ETO CCE CGG GCC TCC ETG CCE CGG GCC 5 TC CET GC CO GC TC CT GC GCG G TCT GEG CTC CTC TEE 60 CTG TGC BCC TEE CEC TOT GET CCE CTE GEC

GGG

GG

G

TCT GTE CTC EEC TCE CCT G TGC TCC TCE CEE CTG GO H:\Gabriela\Keep\Speci\93951-9Sdo 05/07/02 45 Table 3: MTA Oligos, Location Targeted Target (Cont'd) MTA Oligo SEQ. ID Location Compound Target No. Taraeted CTC CTC TBG CCT GG 2371 EPI-2195-06 HSNBARKS4 ct-adr rec k ina se GTG CTC CBE TCE ECT GGG 2372 EPI-2195-07 HSTNFR2SO6 ThF R2 GTG CBC CBE TCB CCT GGG 2373 EPI-2195-08 humfkbp fk506 bindinig protein TCT GTG CBC CTC TEG ECT 2374 exon EPI-2195-09 HSNBARKS1 adrReceptor kinase CTG TEE TCC TEE CEC CTG G 2429 intron EPI-2195-10 HUMIL8 TGT GCT EET CEC ECE TGG G 2376 EPI-2195-11 HSU50157 PDE4 GTG CEC CEC TCE CCT G 2377 intron/exon EPI-2195-12 IL-2 R CTG TGC ECC TCT C 2378 31UTR EPI-2203-05 IL-6 R HSIL6R CEG TGC ECC ECT CEC CTG 2379 intr/ex EPI-2203-06A HSIL2rG6 G TGC ECC ECT CEC CTG 2377 intr/ex EPI-2203-06B HSIL2rG6 CEC CTC TCE CCT GGG 2381 coding EPI-2203-07A HUMIL71 C CTC TCE CCT GGG 2382 coding EPI-2203-07B IL-7 HUMIL71 GCT CCE CTC GCC T 2383 coding EPI-2203-08 IL-6 R HS16REC TGC TCC TCE CGC C 2384 intron PDGF A EPI-2303-09 chain

HUMPDGFAB

GTT GTT GET CTG G 2385 3utr EPI-2199-01 GATA-4 transcrip. Factor for GGT TGE EET TGG TCT TGG 2386 Coding EPI-2199-02 TNFctHUMTNFA GGT TGT TGE TGE TCT G 2387 Far 5UTR EPI-2199-03 HSSUBPlG (Sub P r) GGG TTE EEG TTG ETC TGG 2389 Coding EPI-2199-04 Neurohi1Adh GGG TTE EEG TTG ETC TGG 2388 HSHM2 EPI-2199-05 m2MuscarinicR TTG TTG TEG ETC TGG 2390 HUMLiCAM EPI-2199-06 Li leuk.

adh. prot.

GGG TEG EEG EGT CCG CTG 2391 coding EPI-2203-01 HUGATA2A GGG TCE GEG GET CEG CTG 2392 S7142 S2 EPI-2203-02 IGE eps GGG TEG GTG GGT C 2393 coding EPI-2203-03 HSGCS R2 GGG TCG GEG GGT CEG C 2394 HLTMITGF EPI-2203-04 TGFI3 CCT GGG TGG GCT T 2395 HUMNK65PRO EPI-2206-01 NFKB/NK&T GGG TGG GCT TGG G 2396 HUMPEREEB EPI 2206-02 NFKB7 Pros tagi.

EP3 Receptor a H:\Gabriela\Kee\Speci\93951I-98.doc 05/07/02 WO 99/13886 PCT/US98/1 9419 Table 3: MTA Oligos, Location Targeted Target (Cont'd) MTA Oligo SEQ. ID Location Compound Target No. Targeted

CCTGGGTGGGBBTGGG

CCTGGBTGGGCBTGGG

GCCTGBGTGBBCTTGGG

CCCAVGVCCVCCCAGGC

AGCCCACCCAGGC

BCCTGGGTGGGCTB

GGTGGGCTTGGG

CCBBGGTGGGCTTGGG

CTGGGTGGGBBTGGG

CCBGGGTGGGCTTGG

GGGTGGGCTTGG

CCTGBGTGBGCBTGGG

2397 2398 2399 2400 2401 2402 2403 2404 2405 2406 2407 2408 EPI 2206-03 EPI-2206-04 EPI 2206-05 EPI 2206-06 EPI 2206-07 EPI 2206-08 EPI 2206-09 EPI 2206-10 EPI 2206-11 GCSFR1 EPI 2206-12 EPI-2206-12B EPI 2206-13 HSNF2B/GCSF

NFKB/

Granulocyte CSF/Transcr.

Factor NF2B HUMLAp/NFKB Leuk.Adhes.

Prot.

NFKB/

Endothelime N2 S63833 NFKBAS13 lB Lymph. Ser Thr Prot. Kinase NFKBAS13 /GCSFl HSGCSFR1 Rec.

NFKBAS13 /GCSF1 /NK7TCELLACT.

Prot.

NFK3AS 13 /HSTGFB1 TGFB NFKBAS13 /HSTGFB1 TGFB1 NFKBASl3 HSGCSFR1 NFKBAS13/ HUJMCD3 OA Lymph.Act.

Antig. (Coding) NFKBAS13/ NFKBAS 13 HUNCAM1V Vasc. Endoth.

Cell1 Adh. Molec.

B: Universal Base The MTA oligos of Table 3 are suitable for use with two or more of the targets listed in Table 4 below.

76.

WO 99/13886 PCT/US98/19419 Table 4: Targets for the MTA Oligos of Table 3 Compound Target EPI 2010 Adenosine Al receptor EPI 2045 Adenosine A3 receptor EPI 2873. EPI 2193

NFKB

EPI 1873 Interleukin-1 EPI 1857 Interleukin EPI 2945 Interleukin -4 EPI 2977 Interleukin -8 EPI 2031 EPI 1898 Leukotriene C-4 Synthase EPI 1856 Eotaxin EPI 1131

ICAM

EPI 1085

VCAM

EPI 2085 TNFa EPI 1908

PAF

EPI 1925 IL-4 receptor EPI 2643 P2 aderenergic receptor kinase EPI 2934 Tryptase EPI 2033 Major Basic Protein EPI 2795 Eosinophil Peroxidase NfxB: nuclear factor KB ICAM: intracellular adhesion molecule S VCAM: vascular cell adhesion molecule TNF: tumor necrosis factor PAF: platelet activating factor In a most preferred embodiment for use in the lung, the MTA oligo of this invention comprises a desadenosine oligonucleotide, whether an anti-sense to a naturally occurring desthymidine sequence, or by substitution with one or more universal bases in accordance with the invention. The methods for substituting nucleotide, as well as for synthesizing oligonucleotides of a specific sequence, and which bases to employ as universal bases are known in the art, and need not be further provided here, since they are within the knowledge of an artisan.

In a further embodiment of the agent of the invention, the MTA oligo is operatively linked to an agent or molecule which, itself, is internalized or up-taken by living cells. In this manner, the uptake of the agent of the invention is enhanced as is known in the art. Examples of agents or molecules suitable for use with the MTA oligos of this invention are transferrin, asialoglycoprotein, and streptavidin. Others, however, are also suitable.

The present agents are also provided as a pharmaceutical composition comprising an anti-sense oligonucleotide as given above in an amount effective to reduce expression of a target mRNA, by passing through a cell membrane and binding specifically with target mRNA in the cell so as to prevent its translation are another aspect of the present invention. Such compositions are provided in a suitable pharmaceutically acceptable carrier, e.g. sterile pyrogen-free saline solution. The agent of the invention may be formulated with a hydrophobic carrier capable of passing through a cell membrane, e.g. in a liposome, with the liposomes 77 WO 99/13886 PCT/US98/19419 carried in a pharmaceutically acceptable aqueous carrier. The oligonucleotides may be coupled to an agent which inactivates mRNA, such as a ribozyme. Such oligonucleotides may be administered to a subject in need of such treatment to inhibit the activation of specific receptors, enzymes and/or proteins and/or factors, among other expression products. The pharmaceutical formulation may also comprise chimeric molecules comprising anti-sense oligonucleotides attached to molecules which are known to be internalized by cells. These oligonucleotide conjugates utilize cellular up-take pathways to increase intracellular concentrations of the oligonucleotide. Examples of molecules used in this manner are macromolecules including transferrin, asialoglycoprotein (bound to oligonucleotides via polylysine) and streptavidin, among others.

The anti-sense compound may be contained in the pharmaceutical formulation within a lipid particle or vesicle, such as a liposome or microcrystal. The particles may be of any suitable structure, such as unilamellar or plurilamellar. The one preferred embodiment, the anti-sense oligonucleotide is comprised within the liposome. Positively charged lipids such as 3 -dioleoyloxi) propyl] N, N-trimethylammoniumethylsulfate, or "DOTAP," are particularly preferred for such particles and vesicles. However, others are also suitable. The preparation of such lipid particles is well known. See, US Patent Nos. 4,880,635 to Janoff et al., 4,906,477 to Kurono et al., 4,911,928 to Wallach, 4,917,951 to Wallach, 4,920,016 to Allen et al., 4,921,757 to Wheatley et al., the relevant sections of all of which are herein incorporated in their entireties by reference.

The composition of the invention may be administered by any means which transports the agent to the lungs. The present agents may be administered to the lungs of a patient by any suitable means, but are preferably administered through the respiratory system as a respirable formulation, more preferably in the form of an aerosol comprising respirable particles which, in turn, comprise the agent for respiration or inhalation by the subject. The respirable particles may be in gaseous, liquid or solid form, and they may, optionally, contain other therapeutic ingredients and formulation components.

The particles of the present invention are preferably particles of respirable size, preferably of a size sufficiently small to pass, upon inhalation, through the mouth and larynx and into the bronchi and alveoli of the lungs. In general, particles ranging from about 0.5 to microns in diameter are respirable. However, other sizes may also be suitable. Particles of non-respirable size, of considerably larger diameter, which are included in the respirable formulation tend to deposit in the throat and may be swallowed. Accordingly, it is desirable to minimize the quantity of non-respirable particles in the aerosol. For nasal administration, a particle size in the range of 10-500 pm is preferred to ensure their retention in the nasal cavity.

S" 78 WO 99/13886 PCT/US98/19419 Liquid pharmaceutical compositions of the agent of the invention for producing a respirable formulation, e.g. an aerosol may be prepared by combining the anti-sense oligo with a suitable vehicle or carrier, such as sterile pyrogen-free water and/or other known pharmaceutically or veterinarily acceptable carrier. Other therapeutic compounds may be included as well as other formulation ingredients as is known in the art.

Solid particulate compositions comprising respirable dry particles of, e.g. the micronized agent of the invention may be prepared by grinding the dry anti-sense compound with a mortar and pestle, and then passing the thus ground, e.g. micronized composition through a screen, e.g. 400 mesh screen, to break up or separate large agglomerates of particles. A solid particulate composition comprising the anti-sense compound may optionally also comprise a dispersant and other known agents, which serve to facilitate the formation of a mist or aerosol. A suitable dispersant is lactose, which may be blended with the anti-sense compound in any suitable ratio, about 1:1 w/w. Other ratios may be utilized as well, and other therapeutic and formulation agents may also be included.

Aerosols of liquid particles comprising the agent may be produced by any suitable means, such as with an insufflator or nebulizer. See, US Patent No. 4,501,729.

Nebulizers are commercially available devices which transform solutions or suspensions of an agent into a therapeutic aerosol mist either by means of acceleration of a compressed gas, typically air or oxygen, e.g. through a narrow venturi orifice or by means of ultrasonic agitation. Suitable formulations for use in insufflators and nebulizers comprise the present agent, the agent of this invention, in an amount of about 0.01 to about 40%, preferably less than 20% w/w in a liquid carrier which is typically water or a dilute aqueous alcoholic solution, preferably made isotonic with body fluids by the addition of, for example, sodium chloride. Other carriers are also suitable. Optional additives include preservatives if the formulation is not prepared sterile, for example, methyl hydroxybenzoate, antioxidants, flavoring agents, volatile oils, buffering agents and surfactants, among others.

The pharmaceutical compositions provided herein comprise nucleic acid(s) comprising the anti-sense oligonucleotide(s) described above and one or more surfactants. Suitable surfactants or surfactant components for enhancing the uptake of the anti-sense oligonucleotides of the invention include synthetic and natural as well as full and truncated forms of surfactant protein A, surfactant protein B, surfactant protein C, surfactant protein D and surfactant Protein E, di-saturated phosphatidylcholine (other than dipalmitoyl), dipalmitoylphosphatidylcholine, phosphatidylcholine, phosphatidylglycerol, phosphatidylinositol, phosphatidylethanolamine, phosphatidylserine; phosphatidic acid, .ubiquinones, lysophosphatidylethanolamine, lysophosphatidylcholine, palmitoyl-lysophosphatidylcholine, dehydroepiandrosterone, dolichols, sulfatidic acid, WO 99/13886 PCT/US98/19419 glycerol-3-phosphate, dihydroxyacetone phosphate, glycerol, glycero-3-phosphocholine, dihydroxyacetone, palmitate, cytidine diphosphate (CDP) diacylglycerol, CDP choline, choline, choline phosphate; as well as natural and artificial lamelar bodies which are the natural carrier vehicles for the components of surfactant, omega-3 fatty acids, polyenic acid, polyenoic acid, lecithin, palmitinic acid, non-ionic block copolymers of ethylene or propylene oxides, polyoxypropylene, monomeric and polymeric, polyoxyethylene, monomeric and polymeric, poly (vinyl amine) with dextran and/or alkanoyl side chains, Brij 35, Triton X-100 and synthetic surfactants ALEC, Exosurf, Survan and Atovaquone, among others. These surfactants may be useed either as single or part of a multiple component surfactant in a formulation, or as covalently bound additions to the 5' and/or 3' ends of the anti-sense oligonucleotides (oligos).

The composition of the invention may be administered by any means which transports the anti-sense nucleotide and the surfactant composition to the lung. The anti-sense compounds disclosed herein may be administered to the lungs of a patient by any suitable means, but are preferably administered by inhalation of an aerosol comprised of respirable particles which comprise the anti-sense compound. The respirable particles may be liquid or solid, and they may optionally contain other therapeutic or diagnostic ingredients as well as other typical ingredients for a particular formulation. Examples of other agents are analgesics such as acetaminophen, anilerdine, aspirin, buprenorphine, butabital, butorpphanol, Choline Salicylate, Codeine, Dezocine, Diclofenac, Diflunisal, Dihydrocodeine, Elcatoninin, Etodolac, Fenoprofen, Hydrocodone, Hydromorphone, Ibuprofen, Ketoprofen, Ketorolac, Levorphanol, Magnesium Salicylate, Meclofenamate, Mefenamic Acid, Meperidine, Methadone, Methotrimeprazine, Morphine, Nalbuphine, Naproxen, Opium, Oxycodone, Oxymorphone, Pentazocine, Phenobarbital, Propoxyphene, Salsalate, Sodium Salicylate, Tramadol and Narcotic analgesics in addition to those listed above. See, Mosby's Physician's GenRx. Antianxiety agents are also useful including Alprazolam, Bromazepam, Buspirone, Chlordiazepoxide, Chlormezanone, Clorazepate, Diazepam, Halazepam, Hydroxyzine, Ketaszolam, Lorazepam, Meprobamate, Oxazepam and Prazepam, among others. Anti-anxiety agents associated with mental depression, such as Chlordiazepoxide, Amitriptyline, Loxapine Maprotiline and Perphenazine, among others. Anti-inflammatory agents such as non-rheumatic Aspirin, Choline Salicylate, Diclofenac, Diflunisal, Etodolac, Fenoprofen, Floctafenine, Flurbiprofen, Ibuprofen, Indomethacin, Ketoprofen, Magnesium Salicylate, Meclofenamate, Mefenamic Acid, Nabumetone, Naproxen, Oxaprozin, Phenylbutazone, Piroxicam, Salsalate, Sodium Salicylate, Sulindac, Tenoxicam, Tiaprofenic Acid, Tolmetin, anti-inflammatories for ocular treatment such as Diclofenac, Flurbiprofen, Indomethacin, Ketorolac, Rimexolone (generally for post-operative treatment), anti-inflammatories for, non-infectious nasal S WO 99/13886 PCT/US98/19419 applications such as Beclomethaxone, Budesonide, Dexamethasone, Flunisolide, Triamcinolone, and the like. Soporifics (anti-insomnia/sleep inducing agents) such as those utilized for treatment of insomnia, including Alprazolam, Bromazepam, Diazepam, Diphenhydramine, Doxylamine, Estazolam, Flurazepam, Halazepam, Ketazolam, Lorazepam, Nitrazepam, Prazepam Quazepam, Temazepam, Triazolam, Zolpidem and Sopiclone, among others. Sedatives including Diphenhydramine, Hydroxyzine, Methotrimeprazine, Promethazine, Propofol, Melatonin, Trimeprazine, and the like. Sedatives and agents used for treatment of petit mal and tremors, among other conditions, such as Amitriptyline HCI; Chlordiazepoxide, Amobarbital; Secobarbital, Aprobarbital, Butabarbital, Ethchiorvynol, Glutethimide, L-Tryptophan, Mephobarbital, MethoHexital Na, Midazolam Hcl, Oxazepam, Pentobarbital Na, Phenobarbital, Secobarbital Na, Thiamylal Na, and many others. Agents used in the treatment of head trauma (Brain Injury/Ischemia), such as Enadoline HCI for treatment of severe head injury; orphan status, Warner Lambert), cytoprotective agents, and agents for the treatment of menopause, menopausal symptoms (treatment), e.g. Ergotamine, Belladonna Alkaloids and Phenobarbital, for the treatment of menopausal vasomotor symptoms, e.g. Clonidine, Conjugated Estrogens and Medroxyprogesterone, Estradiol, Estradiol Cypionate, Estradiol Valerate, Estrogens, conjugated Estrogens, esterified Estrone, Estropipate, and Ethinyl Estradiol. Examples of agents for treatment of pre menstrual syndrome (PMS) are Progesterone, Progestin, Gonadotrophic Releasing Hormone, Oral contraceptives, Danazol, Luprolide Acetate, Vitamin B6. Examples of agents for treatment of emotional/psychiatric treatments such as Tricyclic Antidepressants, including Amitriptyline HCI (Elavil), Amitriptyline HC1, Perphenazine (Triavil) and Doxepin HCI (Sinequan). Examples of tranquilizers, antidepressants and anti-anxiety agents are Diazepam (Valium), Lorazepam (Ativan), Alprazolam (Xanax), SSRI's (selective Ssrotonin reuptake inhibitors), Fluoxetine HCI (Prozac), Sertaline HC1 (Zoloft), Paroxetine HCI (Paxil), Fluvoxamine Maleate (Luvox), Venlafaxine HCI (Effexor), Serotonin, Serotonin Agonists (Fenfluramine), and other over the counter (OTC) medications.

The composition of the present invention may be administered into the respiratory system as a formulation including particles of respirable size, e.g. particles of a size sufficiently small to pass through the nose, mouth and larynx upon inhalation and through the bronchi and alveoli of the lungs. In general, respirable particles range from about 0.5 to microns in size; Particles of non-respirable size which are included in the aerosol tend to deposit in the throat and be swallowed, and the quantity of non-respirable particles in the aerosol is thus minimized. For nasal administration, a particle size in the range of 10-500 pm is preferred to ensure retention in the nasal cavity.

81 WO 99/13886 PCT/US98/19419 Aerosols or mists of solid particles comprising the agent of the invention may likewise be produced with any device that generates solid particulate medicament aerosols or mists.

Aerosol and mist generators are suitable for administering solid particulate medicaments.

These devices produce respirable particles, as explained above., and generate a volume of aerosol or mist containing a predetermined metered dose of a medicament at a rate suitable for human or animal administration. One illustrative type of solid particulate aerosol generator is an insufflator. Suitable formulations for administration by insufflation include finely comminuted powders which may be delivered by means of an insufflator or taken into the nasal cavity in the manner of a snuff. In the insufflator, the powder, e.g. a metered dose of the agent effective to carry out the treatments described herein, is contained in a capsule or a cartridge.

These capsules or cartridges are typically made of gelatin or plastic, and may be pierced or opened in situ, and the powder delivered by air drawn through the device upon inhalation or by means of a manually-operated pump. The powder employed in the insufflator may consist either solely of the agent or of a powder blend comprising the agent, a suitable powder diluent, such as lactose, and an optional surfactant as well as other agents. The agent typically comprises from 0.01 to 100 w/w of the formulation. A second type of illustrative aerosol generator comprises a metered dose inhaler. Metered dose inhalers are pressurized aerosol dispensers, typically comprising a suspension or solution formulation of the active ingredient in a liquified propellant. During use these devices discharge the formulation through a valve adapted to deliver a metered volume, typically about 10 to 150 d, although other volumes are also suitable, to produce a fine particle spray containing the active ingredient. Suitable propellants include solvents such as certain chlorofluorocarbon compounds, for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane and/or mixtures thereof. The formulation may additionally comprise one or more co-solvents, for example, ethano!, surfactants, such as oleic acid or sorbitan trioleate, antioxidants and suitable flavoring agents. The aerosol, whether formed from solid or liquid particles, may be produced by the aerosol generator at a rate of from about 10 to 150 liters per minute, more preferably from about 30 to 150 liters per minute, and most preferably about 60 liters per minute. Aerosols containing greater amounts of medicament may be administered more rapidly.

As already indicated, the agent of this invention is also provided as a composition, comprising the agent of the invention, and a carrier. The carrier is preferably a biologically acceptable carrier, and more preferably a pharmaceutically or veterinarily acceptable carrier in the form -of a gaseous, liquid, solid carriers, and mixtures thereof, which are suitable for the different routes of administration intended. The composition may optionally comprise other agents such as other therapeutic compounds known in the art for the treatment of the condition or disease, antioxidants, flavoring and coloring agents, fillers, volatile oils, buffering agents, 82 WO 99/13886 PCT/US98/19419 dispersants, surfactants, RNA inactivating agents, antioxidants, flavoring agents, propellants and preservatives, as well as other agents known to be utilized in therapeutic compositions. An example of the mRNA inactivating agent is an enzyme, such as ribozyme.

The composition generally contains the anti-sense oligonucleotide in an amount of about 0.01 to about 99.99 w/w, preferably about 1 to about 40 w/w, and more preferably about 5 to about 20 w/w of the composition. However, other ingredients, and other amounts of the agent are also suitable within the confines of this invention.

The agent of the invention is also provided in various formulations which are tailored for different methods of administration and routes of delivery. The formulations that are contemplated are, for example, a transdermal formulation also containing carrier(s) and other agents suitable for delivery through the skin, mouth, nose, vagina, anus, eyes, ears, other body cavities, intradermally, as a sustained release formulation, intracranial, intrathecally, intravascularly, by inhalation, intrapulmonarily, into an organ, by implantation, including suppositories, cremes, gels, and the like, as is known in the art. In one particular formulation, the agent is suspended or dissolved in a solvent. In another the carrier comprises a hydrophobic carrier, such as lipid particles or vesicles, including liposomes and micro crystals. The preparation of all of these formulations, as well as the ingredients to be utilized are known in the art, and need not be further described here. In one particularly preferred embodiment of the vesicle formulation, the vesicles comprise liposomes containing the anti-sense oligonucleotide. The lipid vesicles may comprise 2, 3-dioleoxyloxi] propyl) -N,N,Ntrimethyl- ammonium methylsulfate as well as other lipids known in the art to provide suitable delivery of DNA to target cells. In one embodiment, the formulation comprises a respirable formulation, such as an aerosol. The agent, composition, and formulation of the invention are provided in bulk, and in unit form, as well as in the form of an implant, a solution or suspension, a capsule or cartridge, which may be openable or piercable as is known in the art.

A kit is also provided, which comprises a delivery device, and in separate containers, the agent, composition or formulation of the invention, and optionally other agents, and instructions for the use of the kit components. In one preferred embodiment, the delivery device comprises a nebulizer which delivers single or multiple metered doses of the formulation. The single metered dose nebulizer may be provided as a disposable kit which is sterilely preloaded with enough agent for one application. The nebulizer may be provided as an insufflator, and the composition in a piercable or openable capsule or cartridge. In a different embodiment, the delivery device comprises a pressurized inhaler, and the agent is in the form of a suspension or solution. The kit may optionally also comprise in a separate container an agent selected from the group consisting of other therapeutic compounds, antioxidants, flavoring and coloring agents, fillers, volatile oils, buffering agents, dispersants, WO 99/13886 PCT/US98/19419 surfactants, cell internalized or up taken agents, RNA inactivating agents, antioxidants, flavoring agents, propellants and preservatives, among other suitable additives for the different formulations. When a solvent for the agent or the other ingredients is added, organic solvents and organic solvents mixed with one or more co-solvents may be utilized as well as aqueous solvents as is known in the art.

The agent of the invention may be provided in conjunction with a vector for delivery purposes, or for manufacturing copies thereof. The agent may be operatively linked to the vector as is known in the art. The agent may also be provided within a host cell for amplification of the MTA oligo, and for storage purposes.

The agent of this invention may be utilized by itself or in the form of a composition or various formulations in the treatment of a disease or condition associated with the mRNA corresponding to at least one target gene(s), to genomic flanking regions, initiation codon, intron-exon borders and the like, or the entire sequence of precursor RNAs, including noncoding RNA segments, the 5'-end and the 3'-end, e.g. poly-A segment and oligos targeted to the juxta-section between coding and non-coding regions, and RNA regions encoding proteins, by administration to a subject afflicted with the disease or condition of an amount of the antisense oligonucleotide effective to reduce the production or availability, or to increase the degradation by the subject of at least one of the target mRNAs. Typically, the agent is administered in an amount effective to reduce the production or availability, or to increase the degradation of at least two of the target mRNAs. Optionally, the agent is administered directly to the lung of the subject, preferably as a respirable aerosol. Although an artisan will know how to titrate the amount of agent to be administered by the weight of the subjected being treated in accordance with the teachings of this patent, the agent is preferably administered in an amount effective to attain an intracellular concentration of about 0.05 to about 10 JtM multiple targeted anti-sense oligonucleotide, preferably in an amount effective to attain an intracellular concentration of up to about 5 1M multiple targeted anti-sense oligonucleotide.

The treatment provided in this patent is suitable for treating numerous diseases and conditions, and its application is solely limited by the availability of target molecules and their sequences. One type of disease or condition for which this technology is particularly well suited are lung diseases or conditions. For this type of application, at least one of the target mRNA encodes a protein such as the adenosine A, receptor, adenosine A 2 B receptor, adenosine

A

3 receptor, and bradykinin B2 receptor. However, other targets are also suitable. In one application, the disease or condition is associated with obstruction of the subject's airways, in another specifically with asthma, etc. One of the preferred target proteins comprises the NfKB transcription factor, although others which were described above are also suitable. In another preferred application, the disease or condition is associated with inflammation. For this type 84 WO 99/13886 PCT/US98/19419 of application at least one of the target mRNA preferably encodes a protein selected from the group consisting of interleukins, chemokines, Rantes and receptors thereof. Still another application is for treating a disease or condition associated with an allergy. For this application, the mRNA preferably encodes a target selected from the group consisting of an antibody and an antibody receptor. For the application of this technology to a disease or condition associated with a malignancy or cancer, the mRNA preferably encodes a target selected from the group consisting of oncogenes, an immunoglobulin and an antibody receptor.

Depending on the target organ or tissue, the agent of the invention may be delivered in one of many ways, for example, by a transdermal or systemic route, and more specifically orally, intracavitarily, intranasally, intraanally, intravaginally, transdermally, intrabucally, intravenously, subcutaneously, intramuscularly, intratumorously, into a gland, by implantation, intradermally, and many other routes of administration. The formulation may be, in addition, an implant, slow release, transdermal release, sustained release, and coated with one or more macromolecules to avoid destruction of the agent prior to reaching the selected target. The subject that may be treated by the present agent are varied, and include humans and other animals in general, and in particular vertebrates, and amongst these mammals, and more specifically humans, and small and large, wild and domesticated, marine and farm animals, and preferably humans and domesticated and farm animals. In one aspect of the invention, at least one of the target mRNAs and the subject are of the same species, and in a preferred case they are of human origin. However, since in one embodiment mismatched nucleotides are replaced, mismatched species may also be utilized.

The multiple targeted anti-sense oligonucleotide of this invention may be administered in a broad dose range. Preferable is an amount of about 0.005 to about 150 mg/kg body weight per administration, and the agent may be administered from once in an acute treatment to several doses per day, to a continuous administration to maintain the level of a specific molecule. Preferred doses are about 0.01 to about 75 mg/kg body weight, more preferably about 1 to 50 mg/kg body weight. The method may be administered as a prophylactic or therapeutic method.

The agent of the invention may be produced by selecting two or more targets selected from the group consisting of genes, genomic flanking regions, mRNAs and proteins known to be associated with at least one disease or condition; obtaining RNAs selected from the group consisting of RNAs corresponding to the genes, to genomic flanking regions, initiation codon, intron-exon borders and the like, or the entire sequence of RNAs, including non-coding RNA segments, the 5'-end and the 3'-end, e.g. the poly-A segment and oligos targeted to the juxtasection between coding and non-coding regions, and RNA segments encoding the target proteins; selecting a segment of a first RNA which is at least about 60% homologous to a WO 99/13886 PCTIUS98/1 9419 segment of at least a segment of a second RNA; and synthesizing one or more anti-sense oligonucleotide(s) to the one or more RNA segments. In one preferred embodiment, the method further comprises substituting a universal base for at least one, and in some instances all non-homologous nucleotide in the anti-sense oligonucleotide, and in another preferred embodiment the method further comprises substituting a methylated cytosine for cytosine in at least one CpG dinucleotide present in the anti-sense oligonucleotide. The technology involved in methylation is known in the art and need not be further described here.

Although the specific length of the MTA oligo is determined by the target's length, and its segments containing few thymidines, the anti-sense oligonucleotide(s) are preferably greater than about 7 nucleotides long, and up to about 60 nucleotides long, and longer. The specific backbone chemistry may by selected by an artisan based on the teachings provided here and the knowledge of the art at large. One factor that impinges on the selection of the nucleotide bridging residues is the level of nuclease resistance desired and other factors specific to one or the other method of administration. Another factor is the need for localization of the treatment, to minimize or fully avoid side effects which might otherwise be caused along with the therapeutic effect of the agent.

The following examples are provided to illustrate the present invention, and should not be construed as limiting thereon. In these examples, pM means micromolar, ml means milliliters, pM means micrometers, mm means millimeters, cm means centimeters, °C means degrees Celsius, /g means micrograms, mg means milligrams, g means grams, kg means kilograms, M means molar, and h means hours.

EXAMPLES

Example 1: Design and Synthesis of Anti-sense Oligonucleotides The design of anti-sense oligonucleotides against the A, and A 3 adenosine receptors may require the solution of the complex secondary structure of the target A, receptor mRNA and the target A 3 receptor mRNA. After generating this structure, anti-sense nucleotide are designed which target regions of mRNA which might be construed to confer functional activity or stability to the mRNA and which optimally may overlap the initiation codon. Other target sites are readily usable. As a demonstration of specificity of the anti-sense effect, other oligonucleotides not totally complementary to the target mRNA, but containing identical nucleotide compositions on a w/w basis, are included as controls in anti-sense experiments.

The mRNA secondary structure of the adenosine A' receptor was analyzed and used as described above, to design a phosphorothioate anti-sense oligonucleotide. The anti-sense oligonucleotide which was synthesized was designated HAdAAS and had the following sequence: WO 99/13886 PCT/US98/19419 -GAT GGA GGG CGG CAT GGC GGG-3' (SEQ ID NO:1) As a control, a mismatched phosphorothioate anti-sense nucleotide designated HAdAIMM1 was synthesized with the following sequence: -GTA GCA GGC GGG GAT GGG GGC-3' (SEQ ID NO:2) Each oligonucleotide had identical base content and general sequence structure.

Homology searches in GENBANK (release 85.0) and EMBL (release 40.0) indicated that the anti-sense oligonucleotide was specific for the human and rabbit adenosine A, receptor genes, and that the mismatched control was not a candidate for hybridization with any known gene sequence.

The secondary structure of the adenosine A 3 receptor mRNA was similarly analyzed and used as described above to design two phosphorothioate anti-sense oligonucleotides. The first anti-sense oligonucleotide (HAdA3AS1) synthesized had the following sequence: -GTT GTT GGG CAT CT GCC-3' (SEQ ID NO:3) As a control, a mismatched phosphorothioate anti-sense oligonucleotide (HAdA3MM1) was synthesized, having the following sequence: -GTA CTT GCG GAT CTA GGC-3' (SEQ ID NO:4) A second phosphorothioate anti-sense oligonucleotide (HAdA3AS2) was also designed and synthesized, having the following sequence: -GTG GGC CTA GCT CTC GCC-3' (SEQ ID Its control oligonucleotide (HAdA3MM2) had the sequence: -GTC GGG GTA CCT GTC GGC-3' (SEQ ID NO:6) Phosphorothioate oligonucleotides were synthesized on an Applied Biosystems Model 396 Oligonucleotide Synthesizer, and purified using NENSORB chromatography (DuPont,

MD).

Example 2: In Vivo Testing of Adenosine A, Receptor Anti-sense Oligos The anti-sense oligonucleotide against the human A, receptor (SEQ ID NO:1) described above, was tested for efficacy in an in vitro model utilizing lung adenocarcinoma cells HTB- 54. HTB-54 lung adenocarcinoma cells were demonstrated to express the A, adenosine receptor using standard northern blotting procedures and receptor probes designed and synthesized in the laboratory.

HTB-54 human lung adenocarcinoma cells (106/100 mm tissue culture dish) were exposed to 5.0 iM HAdA1AS or HAdAlMM1 for 24 hours, with a fresh change of media and oligonucleotides after 12 hours of incubation. Following 24 hour exposure to the oligonucleotides, cells were harvested and their RNA extracted by standard procedures. A 21mer probe corresponding to the region of mRNA targeted by the anti-sense (and therefore WO 99/13886 PCT/US98/19419 having the same sequence as the anti-sense, but not phosphorothioated) was synthesized and used to probe northern blots of RNA prepared from HAdA1AS-treated, HAdAIMM1-treated and non-treated HTB-54 cells. These blots showed clearly that HAdAIAS but not HAdAIMM1 effectively reduced human adenosine receptor mRNA by This result showed that HAdAIAS is a good candidate for an anti-asthma drug since it depletes intracellular mRNA for the adenosine A, receptor, which is involved in asthma.

Example 3: In Vivo Efficacy of Adenosine

A

1 Receptor Anti-sense Oligos A fortuitous homology between the rabbit and human DNA sequences within the adenosine A, gene overlapping the initiation codon permitted the use of the phosphorothioate anti-sense oligonucleotides initially designed for use against the human adenosine A, receptor in a rabbit model.

Neonatal New Zealand white Pasteurella-free rabbits were immunized intraperitoneally within 24 hours of birth with 312 antigen units/ml house dustmite farinae) extract (Berkeley Biologicals, Berkeley, CA), mixed with 10% kaolin. Immunizations were repeated weekly for the first month and then biweekly for the next 2 months. At 3-4 months of age, eight sensitized rabbits were anesthetized and relaxed with a mixture of ketamine hydrochloride (44 mg/kg) and acepromazine maleate (0.4 mg/kg) administered intramuscularly.

The rabbits were then laid supine in a comfortable position on a small molded, padded animal board and intubated with a 4.0-mm intratracheal tube (Mallinkrodt, Inc., Glens Falls, NY). A polyethylene catheter of external diameter 2.4 mm with an attached latex balloon was passed into the esophagus and maintained at the same distance (approximately 16 cm) from the mouth throughout the experiments. The intratracheal tube was attached to a heated Fleisch pneumotachograph (size 00; DOM Medical, Richmond, VA), and flow was measured using a Validyne differential pressure transducer (Model DP-45161927; Validyne Engineering Corp., Northridge, CA) driven by a Gould carrier amplifier (Model 11-4113; Gould Electronic, Cleveland, OH). The esophageal balloon was attached to one side of the differential pressure transducer, and the outflow of the intratracheal tube was connected to the opposite side of the pressure transducer to allow recording of transpulmonary pressure. Flow was integrated to give a continuous tidal volume, and measurements of total lung resistance (RL) and dynamic compliance (Cdyn) were calculated at isovolumetric and flow zero points, respectively, using .an automated respiratory analyzer (Model 6; Buxco, Sharon, CT).

Animals were randomized and on Day 1 pretreatment values for PC50 were obtained for aerosolized adenosine. Anti-sense (HAdAlAS) or mismatched control (HAdAIMM) oligonucleotides were dissolved in sterile physiological saline at a concentration of 5000 jzg 88 WO 99/13886 PCT/US98/19419 mg) per 1.0 ml. Animals were subsequently administered the aerosolized anti-sense or mismatch oligonucleotide via the intratracheal tube (approximately 5000 yg in a volume of ml), twice daily for two days. Aerosols of either saline, adenosine, or anti-sense or mismatch oligonucleotides were generated by an ultrasonic nebulizer (DeVilbiss, Somerset, PA), producing aerosol droplets 80% of which were smaller than 5 tm in diameter.

In the first arm of the experiment, four randomly selected allergic rabbits were administered anti-sense oligonucleotide and four the mismatched control oligonucleotide. On the morning of the third day, PC50 values (the concentration of aerosolized adenosine in mg/ml required to reduce the dynamic compliance of the bronchial airway 50% from the baseline value) were obtained and compared to PC50 values obtained for these animals prior to exposure to oligonucleotide.

Following a 1 week interval, animals were crossed over, with those previously administered mismatch control oligonucleotide now administered anti-sense oligonucleotide, and those previously treated with anti-sense oligonucleotide now administered mismatch control oligonucleotide. Treatment methols and measurements were identical to those employed in the first arm of the experiment. It should be noted that in six of the eight animals treated with anti-sense oligonucleotide, adenosine-mediated bronchoconstriction could not be obtained up to the limit of solubility of adenosine, 20 mg/ml. For the purpose of calculation, values for these animals were set at 20 mg/ml. The values given therefore represent a minimum figure for anti-sense effectiveness. Actual effectiveness was higher. The results of this experiment are illustrated in Table 3 below.

89 t- WO 99/13886 PCT/US98/19419 TIale 3: Effect of Adenosine A, Receptor Anti-sense Oligo upon PC50 Values in Asthmatic Rabbits Mismatch Control A, Receptor Anti-sense Oligo Pre Oligonucleotide Post Oligonucleotide re Oligonucleotide Post Oligonucleotide .56 1.02 5.16 1.03 .36 0.68 >19.5 0.34** The results are presented as the mean SEM.

The significance was determined by repeated-measures analysis of variance (ANOVA), and Tukey's protected test.

*Significantly different from all other groups, p<0.01.

In both arms of the experiment, animals receiving the anti-sense oligonucleotide showed an order of magnitude increase in the dose of aerosolized adenosine required to reduce dynamic compliance of the lung by 50%. No effect of the mismatched control oligonucleotide upon PC50 values was observed. No toxicity was observed in any animal receiving either anti-sense or control inhaled oligonucleotide.

These results show clearly that the lung has exceptional potential as a target for antisense oligonucleotide-based therapeutic intervention in lung disease. They further show, in a model system which closely resembles human asthma, that downregulation of the adenosine A, receptor largely eliminates adenosine-mediated bronchoconstriction in asthmatic airways.

Bronchial hyperresponsiveness in the allergic rabbit model of human asthma is an excellent endpoint for anti-sense intervention since the tissues involved in this response lie near to the point of contact with aerosolized oligonucleotides, and the model closely simulates an important human disease.

Example 4: Specificity of At-adenosine Receptor Anti-sense Oligonucleotide At the conclusion of the cross-over experiment of Example 3 above, airway smooth muscle from all rabbits was quantitatively analyzed for adenosine A, receptor number. As a control for the specificity of the anti-sense oligonucleotide, adenosine A 2 receptors, which should not have been affected, were also quantified.

Airway smooth muscle tissue was dissected from each rabbit and a membrane fraction prepared according to the method of Kleinstein et al. (Kleinstein, J. and Glossmann, H., Naunyn-Schmiedeberg's Arch. Pharmacol. 305: 191-200 (1978)), the relevant portion of which is hereby incorporated in its entirety by reference, with slight modifications. Crude plasma membrane preparations were stored at 70 0 C until the time of assay. Protein content was determined by the method of Bradford Bradford, Anal. Biochem. 72, 240-254 (1976), the relevant portion of which is hereby incorporated in its entirety by reference). Frozen plasma WO 99/13886 PCT/US98/19419 membranes were thawed at room temperature and were incubated with 0.2 U/ml adenosine deaminase for 30 minutes at 37°C to remove endogenous adenosine. The binding of [H] DPCPX receptor-specific) or [3H] CGS-21680 receptor-specific) was measured as previously described by Ali et al. (Ali, S. et al., J. Pharmacol. Exp. Ther. 268, Am. J. Physiol 266, L271-277 (1994), the relevant portion of which is hereby incorporated in its entirety by reference).

The animals treated with adenosine A 1 anti-sense oligonucleotide in the cross-over experiment had a nearly 75% decrease in A, receptor number compared to controls, as assayed by specific binding of the A,-specific antagonist DPCPX. There was no change in adenosine

A

2 receptor number, as assayed by specific binding of the A 2 receptor-specific agonist 2- [p- (2-carboxyethyl)-phenethylamino] (N-ethylcarboxamido) adenosine (CGS-21680). This is illustrated in Table 4 below.

Table 4: Specificity of Action of Adenosine A, Receptor Anti-sense Oligonucleotide Mismatch Control A 1 Anti-sense Oligonucleotide Oligonucleotide Ai-Specific Binding 1105 48** 293 18

A

2 -Specific Binding 302 22 442 171 The results are presented as the mean (n 8) SEM.

The significance was determined by repeated-measures analysis of variance (ANOVA), and Tukey's protected test.

**Significantly different from mismatch control, p<0.01.

The above results illustrate the effectiveness of anti-sense oligonucleotides in treating airway disease. Since the anti-sense oligos described above, eliminate the receptor systems responsible for adenosine-mediated bronchoconstriction, it may be less imperative to eliminate adenosine from them. However, it would be preferable to eliminate adenosine from even these oligonucleotides to reduce the dose needed to attain a similar effect. Described above are other anti-sense oligonucleotides targeting mRNA of proteins involved in inflammation. Adenosine has been eliminated from their nucleotide content to prevent its liberation during degradation.

Example 5: Anti-sense Oligos directed to other Target Nucleic Acids This work was conducted to demonstrate that the present invention is broadly applicable to anti-sense oligonucleotides ("oligos") specific to nucleic acid targets broadly. The following experimental studies were conducted to show that the method of the invention is broadly suitable for use with anti-sense oligos designed as taught by this application and targeted to any 92 and all adenosine receptor mRNAs. For this purpose, various anti-sense oligos were porepared to adenosine receptor mRNAs exemplified by the adenosine An, A2b and A 3 receptor mRNAs. Anti-sense Oligo I was disclosed above (SEQ. ID NO:1).Five additional anti-sense phosphorothioate oligos were designed asnd synthesized as indicated above.

1- Oligo II (SEQ. ID NO: 7) also targeted to the adenosine AI receptor, but to a different region than Oligo I.

2- Oligo V (SEQ. ID NO: 10) targeted to the adenosine A2b receptor.

3- Oligos III (SEQ. ID NO: 8) and IV (SEQ. ID NO: 9) targeted to different regions of the adenosine A 3 receptor.

4- Oligo I-PD (SEQ. ID NO: 1)(a phosphodiester oligo of the same sequence as Oligo I).

These anti-sense oligos were designed for therapy on a selected species as described above and are generally specific for that species, unless the segment of the target mRNA of other species happens to contain a similar sequences. All anti-sense oligos were prepared as described below, and tested in vivo in a rabbit model for bronchoconstriction, inflammation and allergy, which have breathing difficulties and impeded lung airways, as is the case in ailments such as asthma, as described in the above-identified application.

Example 6: Design Sequences of other Anti-sense Oligos Six oligos and their effects in a rabbit model were studied and the results of these studies are reported and discussed below. Five of these oligos were selected for this study to complement the data on Oligo I (SEQ ID NO: 1) provided in Examples 1 to 4 above. This oligo is anti-sense to one region of the adenosine AI receptor mRNA. The oligos tested are identified as anti-sense Oligos I (SEQ ID NO: 1) and II (SEQ. ID No: 7) targeted to a different region of the adenosine A, receptor mRNA, Oligo V (SEQ. ID No:8) targeted to the adenosine A2b receptor mRNA, and anti-sense Oligos III and IV (SEQ. ID NOS: 9 and 10) targeted to two different regions of the adenosine A 3 receptor mRNA. The sixth oligo (Oligo I-PD) is a phosphodiester version of Oligo I (SEQ. ID NO:1). The design and synthesis of these anti-sense oligos was o performed in accordance with Example 1 above.

Anti-sense Oligo I The anti-sense oligonucleotide I referred to in Examples 1 to 4 above is targeted to the human A, adenosine receptor mRNA (EPI 2010). Anti-sense oligo I is 21 nucleotide long, overlaps the initiation 30 codon, and has the following sequence. GAT GGA GGG CGG CAT GGC GGG (:SEQ. ID No 1).

The oligo I was previously shown to abrogate the adenosine-induced bronchoconstriction in allergic rabbits, and to reduce allergen-induced airway obstruction and a *o* o* •go• H:\Gabricla\Keep\peci939S I-98.doc 05/07/02 bronchial hyperresponsiveness (BHR), as discussed above and shown by Nyce, J. W. Metzger, W. J., Nature, 385:721 (1977), the relevant portions of which reference are incorporated in their entireties herein by reference.

(II) Anti-sense Oligo II A phosphorothioate anti-sense oligo (SEQ. ID NO:7) was designed in accordance with the invention to target the rabbit adenosine A, receptor mRNA region +936 to +956 relative to the initiation codon (start site). The anti-sense oligo II is 21 nucleotide long, and has the following sequence: GTC GCC GTC GCC GGC GGG-3' (SEQ. ID NO:7).

(Ill) Anti-sense Oligo III A phosphorothioate anti-sense oligo other than that provided in Example 1 above (SEQ. ID NO:8) was designed in accordance with the invention to target the anti-sense A 3 receptor mRNA region +3 to 22 relative to the initiation codon start site. The anti-sense oligo III is 20 nucleotide long, and has the following sequence: 5'-GGG TGG TGC TAT TGT CGG GC-3' (SEQ. ID NO:8).

(IV) Anti-sense Oligo IV Yet another phosphorothioate anti-sense oligo (SEQ. ID NO:9) was designed in accordance with the invention to target the adenosine A 3 receptor mRNA region 386 to 401 relative to the initiation codon (start site). The anti-sense oligo IV is 15 nucleotide long, and has the following sequence: 5'-GGC CCA GGG CCA GCC-3' (SEQ. ID NO:9).

Anti-sense Oligo V A phosphorothioate anti-sense oligo (SEQ. ID NO:10) was designed in accordance with the invention to target the adenosine A2b receptor mRNA region -21 to -1 relative to the initiation codon (start site). The anti-sense oligonucleotide V is 21 nucleotide long, and has the following sequence: 5'-GGC CGG GCC AGC CGG GCC CGG-3' (SEQ. ID (VI) A, Mismatch Oligos 25 Two different mismatched oligonucleotides having the following sequences were used as controls for anti-sense oligo I (SEQ. ID NO: 1) described in Example 5 above: A, MM2 5'-GTA GGT GGC •GGG CAA GGC GGG-3' (SEQ. ID NO:2431); A, MM3 5'-GAT GGA GGC GGG CAT GGC GGG- 3' (SEQ. ID NO:2432). Anti-sense oligo I and the two mismatch anti-sense oligos had identical base content and general sequence structure. Homology searches in GENBANK (release 85.0) and EMBL (release 40.0) indicated that the anti-sense oligo I was specific, not only for the human, but also for the rabbit, adenosine A, receptor genes, and that the mismatched controls were not candidates for hybridization with any known human or animal gene sequence.

a H:\GabriciaKeep\Spec\93951-98.doc 05/07/02 94 (VII) Anti-sense Oligo Ai-PD (Oligo VI) A phosphodiester anti-sense oligo (Oligo VI; SEQ. ID NO:1) having the same nucleotide sequence as Oligo I was designed as disclosed in the above-identified application. Anti-sense oligo I-PD is 21 nucleotide long, overlaps the initiation codon, and has the following sequence: GAT GGA GGG CGG CAT GGC GGG (SEQ. ID NO:1).

III) Controls Each rabbit was administered 5.0 ml aerosolized sterile saline following the same schedule as for the anti-sense oligos in (III), and (IV) above.

Example 7: Synthesis of Anti-sense Oligos Phosphorothioate anti-sense oligos having the sequences described in above, were synthesized on an Applied Biosystems Model 396 Oligonucleotide Synthesizer, and purified using NENSORB chromatography (DuPont, DE). TETD (tetraethylthiuram disulfide) was used as the sulfurizing agent during the synthesis. Anti-sense oligonucleotide II (SEQ. ID NO:7), anti-sense oligonucleotide III (SEQ. ID NO: 8) and anti-sense oligonucleotide IV (SEQ. ID NO: 9) were each synthesized and purified in this manner.

Example 8: Preparation of Allergic Rabbits Neonatal New Zealand white Pasturella-free rabbits were immunized intraperitoneally within 24 hours of birth with 0.5 ml of 312 antigen units/ml house dust mite (D.farinae) extract (Berkeley Biologicals, Berkeley, CA) mixed with 10% kaolin as previously described (Metzger, W. in Late Phase Allergic Reactions, Dorsch, Ed., CRC Handbook, pp. 347-362, CRC Press, Boca Raton (1990); Ali, Metzger, W. J. and Mustafa, S. Am. J. Resp. Crit. Care Med. 149: 908 (1994)), the relevant portions of which are incorporated in their entireties here by reference. Immunizations were repeated weekly for the first month and then biweekly until the age of 4 months. These rabbits preferentially produce allergen-specific IgE antibody, typically respond to aeroallergen challenge with both an early and late-phase asthmatic response, S°and show bronchial hyper responsiveness (BHR). Monthly intraperitoneal administration of allergen (312 25 units dust mite allergen, as above) continues to stimulate and maintain allergen-specific IgE antibody and BHR. At 4 months of age, sensitized rabbits were prepared for aerosol administration as described by Ali et al. (Ali, Metzger, W. J. and Mustafa, S. Am. J. Resp. Crit. Care Med. 149 (1994)), the relevant section being incorporated in its entirety here by reference.

DOSE-RESPONSE STUDIES H:\Gabricla\Keep\pec093951-98.doc 05/07/02 WO 99/13886 PCT/US98/19419 Example 9: Experimental Setup Aerosols of either adenosine (0-20 mg/ml), or anti-sense or one of two mismatch oligonucleotides (5 mg/ml) were separately prepared with an ultrasonic nebulizer (Model 646, DeVilbiss, Somerset, PA), which produced aerosol droplets, 80% of which were smaller than 51m in diameter. Equal volumes of the aerosols were administered directly to the lungs via an intratracheal tube.

The animals were randomized, and administered aerosolized adenosine. Day 1 pretreatment values for sensitivity to adenosine were calculated as the dose of adenosine causing a 50% loss of compliance (PCo 0 Adenosine). The animals were then administered either the aerosolized anti-sense or one of the mismatch anti-sense oligos via the intratracheal tube ml), for 2 minutes, twice daily for 2 days (total dose, 20 mg). Post-treatment PCs 0 values were recorded (post-treatment challenge) on the morning of the third day. The results of these studies are provided in Example 21 below.

Example 10: Crossover Experiments For some experiments utilizing anti-sense oligo I (SEQ ID NO: 1) and a corresponding mismatch control oligonucleotide A1MM2, following a 2 week interval, the animals were crossed over, with those previously administered the mismatch control AMM2, now receiving the anti-sense oligo I, and those previously treated with the anti-sense oligo I, now receiving the mismatch control AMM2 oligo.

The number of animals per group was as follows. For mismatch AiMM2 (Control 1), n=7, since one animal was lost in the second control arm of the experiment due to technical difficulties, for mismatch AMM3 n=4 (Control 2) and for AjAS anti-sense oligo I, n=8. The AMM3 oligo-treated animals were analyzed separately and were not part of the cross-over experiment. The treatment methods and measurements employed following the cross-over were identical to those employed in the first arm of the experiment.

In 6 of the 8 animals treated with the anti-sense oligo I (SEQ. ID NO: no PC 50 value could be obtained for adenosine doses of up to 20 mg/ml, which is the limit of solubility of adenosine. Accordingly, the PCso values for these animals were assumed to be 20 mg/ml for calculation purposes. The values given, therefore, represent a minimum figure for the effectiveness of the anti-sense oligonucleotides of the invention. Other groups of allergic rabbits (n=4 for each group) were administered 0.5 or 0.05 mg doses of the anti-sense oligo I (SEQ ID NO: or the AMM2 oligo in the manner and according to the schedule described above (the total doses being 2.0 or 0.2 mg). The results of these studies are provided in Example 22 below.

WO 99/13886 PCT/US98/19419 Example 11: Anti-sense Oligo Formulation Each one of anti-sense oligos were separately solubilized in an aqueous solution and administered as described for anti-sense oligo I (SEQ. ID No:1) in above, in four 5 mg aliquots (20 mg total dose) by means of a nebulizer via endotracheal tube, as described above.

The results obtained for anti-sense oligo I and its mismatch controls confirmed that the mismatch controls are equivalent to saline, as described in Example 19 below and in Table 1 of Nyce Metzger, Nature 385, 721-725 (1997). Because of this finding, saline was used as a control for pulmonary function studies employing anti-sense oligos II, III and IV (SEQ. IS NOS; 7, 8 and 9).

Example 12: Specificity of Oligo I for Adenosine A, Receptor (Receptor Binding Studies) Tissue from airway smooth muscle was dissected to primary, secondary and tertiary bronchi from rabbits which had been administered 20 mg oligo I (SEQ ID NO: 1) in 4 divided doses over a period of 48 hours as described above. A membrane fraction was prepared according to the method of Ali et al. (Ali, et al., Am. J. Resp. Crit. Care Med. 149: 908 (1994), the relevant section relating to the preparation of the membrane fraction is incorporated in its entirety hereby by reference).

The protein content was determined by the method of Bradford and plasma membranes were incubated with 0.2 U/ml adenosine deaminase for 30 minutes at 37 0 C to remove endogenous adenosine. See, Bradford, M. M. Anal. Biochem. 72, 240-254 (1976), the relevant portion of which is hereby incorporated in its entirety by reference. The binding of 3 H]DPCPX, 3 H]NPC17731, or 3 H]CGS-21680 was measured as described by Jarvis et al.

See, Jarvis, et al., Pharmacol. Exptl. Ther. 251, 888-893 (1989), the relevant portion of which is fully incorporated herein by reference. The results of this study are shown in Table 8 and discussed in Example 20 below.

Example 13: Pulmonary Function Measurements (Compliance cDw and Resistance) At 4 months of age, the immunized animals were anesthetized and relaxed with 1.5 ml of a mixture of ketamine HCI (35 mg/kg) and acepromazine maleate (1.5 mg/kg) administered intramuscularly. After induction of anesthesia, allergic rabbits were comfortably positioned supine on a soft molded animal board. Salve was applied to the eyes to prevent drying, and they were closed. The animals were then intubated with a 4.0 mm intermediate high-low cuffed Murphy 1 endotracheal tube (Mallinckrodt, Glen Falls, NY), as previously described by Zavala and Rhodes. See, Zavala and Rhodes, Proc. Soc. Exp. Biol. Med. 144: 509-512 96 WO 99/13886 PCT/US98/19419 (1973), the relevant portion of which is incorporated herein by reference in its entirety. A polyethylene catheter of OD 2.4 mm (Becton Dickinson, Clay Adams, Parsippany NJ) with an attached thin-walled latex balloon was passed into the esophagus and maintained at the same distance (approximately 16 cm) from the mouth throughout the experiment. The endotracheal tube was attached to a heated Fleisch pneumotach (size 00; DEM Medical, Richmond, VA), and the flow measured using a Validyne differential pressure transducer (Model DP-45-16- 1927, Validyne Engineering, Northridge, CA), driven by a Gould carrier amplifier (Model 11- 4113, Gould Electronics, Cleveland, OH).

An esophageal balloon was attached to one side of the Validyne differential pressure transducer, and the other side was attached to the outflow of the endotracheal tube to obtain transpulmonary pressure The flow was integrated to yield a continuous tidal volume, and the measurements of total lung resistance and dynamic compliance (Cdyn) were made at isovolumetric and zero flow points. The flow, volume and pressure were recorded on an eight channel Gould 2000 W high-frequency recorder and Cdyn was calculated using the total volume and the difference in P, at zero flow, and R, was calculated as the ratio of Ptp and V at midtidal lung volumes. These calculations were made automatically with the Buxco automated pulmonary mechanics respiratory analyzer (Model 6, Buxco Electronics, Sharon, CT), as previously described by Giles et al. See, Giles et al., Arch. Int. Pharmacodyn. Ther. 194: 213- 232 (1971), the relevant portion of which describing these calculations is incorporated in toto hereby by reference. The results obtained upon administration of oligo II on allergic rabbits are shown and discussed in Example 26 below.

Example 14: Measurement of Bronchial Hyperresponsiveness (BHR) Each allergic rabbit was administered histamine by aerosol to determine their baseline hyperresponsiveness. Aerosols of either saline or histamine were generated using a DeVilbiss nebulizer (DeVilbiss, Somerset, PA) for 30 seconds and then for 2 minutes at each dose employed. The ultrasonic nebulizer produced aerosol droplets of which 80% were 5 micron in diameter. The histamine aerosol was administered in increasing concentrations (0.156 to mg/ml) and measurements of pulmonary function were made after each dose. The B4R was then determined by calculating the concentration of histamine (mg/ml) required to reduce the Cdyn 50% from baseline (PCs 5 Hisamine)- Example 15: Cardiovascular Effect of Anti-sense Oligo I The measurement of cardiac output and other cardiovascular parameters using Cardiomax M utilizes the principal of thermal dilution in which the change in temperature of the blood exiting the heart after a venous injection of a known volume of cool saline is monitored.

A single rapid,injection of cool saline was made into the right atrium via cannulation of the WO 99/13886 PCT/US98/19419 right jugular vein, and the corresponding changes in temperature of the mixed injectate and blood in the aortic arch were recorded via cannulation of the carotid artery by a temperaturesensing miniprobe.

Twelve hours after the allergic rabbits had been treated with aerosols of oligo I (EPI 2010; SEQ. ID NO: 1) as described in above, the animals were anesthetized with 0.3 ml/kg of 80% Ketamine and 20% Xylazine. This time point coincides with previous data showing efficacy for SEQ. ID NO: 1, as is clearly shown by Nyce Metzger, (1997), supra, the pertinent disclosure being incorporated in its entirety here by reference. A thermocouple was then inserted into the left carotid artery of each rabbit, and was then advanced 6.5 cm and secured with a silk ligature. The right jugular vein was then cannulated and a length of polyethylene tubing was inserted and secured.

A thermodilution curve was then established on a Cardiomax" II (Columbus Instruments, Ohio) by injecting sterile saline at 20°C to determine the correctness of positioning of the thermocouple probe. After establishing the correctness of the position of the thermocouple, the femoral artery and vein were isolated. The femoral vein was used as a portal for drug injections, and the femoral artery for blood pressure and heart rate measurements. Once constant baseline cardiovascular parameters were established, Cardiomax" measurements of blood pressure, heart rate, cardiac output, total peripheral resistance, and cardiac contractility were made.

98 Example 16: Duration of Action of Oligo I (SEQ. ID NO: 1) Eight allergic rabbits received initially increasing log doses of adenosine by means of a nebulizer via an intra-tracheal tube as described in above, beginning with 0.156 mg/ml until compliance was reduced by 50% (PC 50 Adenosine) to establish a baseline. Six of the rabbits then received four 5 mg aerosolized doses of (SEQ. ID NO: 1) as described above. Two rabbits received equivalent amounts of saline vehicle as controls. Beginning 18 hours after the last treatment, the PC 50 Adenosine values were tested again. After this point, the measurements were continued for all animals each day, for up to 10 days. The results of this study are discussed in Example 25 below.

Example 17: Reduction of Adenosine A2b Receptor Number by Anti-sense Oligo V Sprague Dawley rats were administered 2.0 mg respirable anti-sense oligo V (SEQ ID three times over two days using an inhalation chamber as described above. Twelve hours after the last administration, lung parenchymal tissue was dissected and assayed for adenosine A2b receptor binding using [311]-NECA as described by Nyce Metzger (1997), supra. Controls were conducted by administration of equal volumes of saline. The results are significant at p<0.05 using Student's paired t test, and are discussed in Example 28 below.

Example 18: Comparison of Oligo I Corresponding Phosphodiester Oligo VI (SEQ. ID NO:1) Oligo I (SEQ ID NO:1) countered the effects of adenosine and eliminated sensitivity to it for adenosine amounte up to 20 mg adenosine/5.0 ml (the limit of solubility of adenosine). Oligo VI (SEQ ID NO:1), the phosphodiester version of the oligonucleotide sequence, was completely ineffective when tested in the same manner. Both compounds have identical sequence, differing only in the presence of phosphorothioate residues in Oligo I (SEQ ID NO:1), and were delivered as an aerosol as described above 25 and in Nyce Metzger (1997), supra. Significantly different at p<0.001, Student's paired t test. The results

I.

are discussed in Example 29 below.

RESULTS OBTAINED FOR ANTI-SENSE OLIGO I (SEQ. ID NO: 1) Example 19: Results of Prior Work The nucleotide sequence and other data for anti-sense oligo I (SEQ. ID NO: which is e

S

H:\Gabriela\Keep\Spec\93951-98.doc 05/07/02 specific for the adenosine A, receptor, were provided above. The experimental data showing the effectiveness of oligo I in down regulating the receptor number and activity were also provided above.

Further information on the characteristics and activities of anti-sense oligo I is provided in Nyce, J. W. and Metzger, W. Nature 385:721 (1997), the relevant parts of which relating to the following results are incorporated in their entireties herein by reference. The Nyce Metzger (1997) publication provided data showing that the anti-sense oligo I (SEQ. ID NO: 1): The anti-sense oligo I reduces the number of adenosine A, receptors in the bronchial smooth muscle of allergic rabbits in a dose-dependent manner as may be seen in Table 5 below.

Anti-sense Oligo I attenuates adenosine-induced bronchoconstriction and allergen-induced bronchoconstriction.

The Oligo I attenuates bronchial hyperresponsiveness as measured by PCs 0 histamine, a standard measurement to assess bronchial hyperresponsiveness. This result clearly demonstrates anti-inflammatory activity of the anti-sense oligo I as is shown in Table 5 above.

As expected, because it was designed to target it, the anti-sense oligo I is totally specific for the adenosine A, receptor, and has no effect at all at any dose on either the very closely related adenosine A 2 receptor or the related bradykinin B 2 receptor. This is seen in Table 5 below.

In contradistinction to the above effects of the Oligo I, the mismatch control molecules MM2 and MM3 (SEQ. ID NO:2431 and SEQ. ID NO:2432) which have identical base composition and molecular weight but differed from the anti-sense oligo I (SEQ ID NO: 1) by 6 and 2 mismatches, respectively. These mismatches, which are the minimum possible while still retaining identical base composition, produced absolutely no effect upon any of the targeted receptors A 2 or B 2 These results, along with a complete lack of prior art on the use of anti-sense oligonucleotides, such as oligo I, targeted to the adenosine A, receptor, are unexpected results. The showings presented in this patent clearly enable and demonstrate the effectiveness, for their intended use, of the claimed agents and method for treating a disease or condition associated with lung airway, such as bronchoconstriction, inflammation, allergy(ies), and the like.

Example 20: Oligo I Significantly Reduces Response to Adenosine Challenge *o *oo oo* *o *g H:\Gabriela\eep\Speci\93951-98.doc 05/07/02 WO 99/13886 PCT/US98/19419 The receptor binding experiment is described in Example 12 above, and the results shown in Table 5 below which shows the binding characteristics of the adenosine A selective ligand 3 H]DPCPX and the bradykinin B -selective ligand 3 H]NPC 17731 in membranes isolated from airway smooth muscle of A, adenosine receptor and B 2 bradykinin receptor anti-sense- and mismatch-treated allergic rabbits.

101 3 WO 99/13886 PCT/US98/19419 Binding Characteristics of Three Anti-Sense Oligos Izraiment- A, receptor B5 2 receptor Kd Bm Kd Bmax Adenosine A, Receptor 2 0 mg 0.

3 6 ±0.029 nM 19+±1.52 fmoles 0.39+:0.031 nM l 4 8 O9foe 2 mg 0.38±0.030 oM 32±2.56 fmoles* 0.41 ±0.028 nM 15.5±+1.08 fmoles 0.2 mg 0.37±+0.030 nM 49±3.43 fmoles 0.34±0.024 nM 15.0± 1.06 fmoles AIMM1 (Control) 2 0Omg 0.

34 ±0.027 rM 52.0±3.64 finales 0.

3 5 +0.024 nMv 14 2 nmg 0.37±+0.033 nM 51.8+3.88 fmoles 0.38±0.028 nM 14.6+ 1.02 fmoles

B

2 A (Bradykinin Receptor) 0.

3 6 ±0.028 nM 45.0±3.15 finales 0.

3 8 ±0.027 nM 8.7±0.62 fmoles* 2 mg 0.39±0.035 nM 44.3 ±2.90 finales 0.34±0.024 nM 11.9±0.76 fmoles** 0.2 mg 0.

4 0+0.028 nMv 47.0+3.76 finales 0.

3 5 +0.028 nM 15.1 ±1.05 finales

B

2 MM (Control) 2 0Omg 0.39±0.031 nM 42.0±2.94 fmnoles 0.

4 1+0.029 nM 14 .0±0.98 finales 2 mg 0.

4 1±0.035 n% 4 0 .0±3.20 fioles 0. 37 ±0.030 nM 1 4 8 ±0.99 fmoles 0.2 mg 0.37±0.029 nM 43.0±3.14 finales 0.

3 6 ±0.025 nM 15.1±1.35 finoles Saline Control 0.37±0.041 46.0±5.21 0.39±0.047 nM 14.2 ±1.35 finales Refers to total oligo administered in four equivalently divided doses over a 48 hour period. Treatments and analyses were performed as describedj in methods. Significance was determined by repeated-measures analysis of variance (ANOVA), and Tukey's protected t test. n 4-6 for all groups.

Significantly different from mismatch control- and saline-treated groups, p<0.001; "*Significanly different from mismatch control- and saline-treated groups, p <0.05.

EXamplt.ZI: Dose-response Effect of Oligo, I Anti-sense oligo I (SEQ ED NO:1) was found to reduce the effect of adenosine administration to the animal in a dose-dependent manner over the dose range tested as shown in Table 6 below.

102 103 Table 6: Dose-Response Effect to Anti-sense Oligo I Total Dose

PC

5 0 Adenosine (mg) (mg Adenosine) Anti-sense Oligo I 0.2 8.32"7.2 14.0"7.2 19.5"0.34 AIMM2 oligo (control) 0.2 2.51"0.46 2.0 3.13" 0.71 3.25" 0.34 The above results were studied with the Student's paired t test and found to be statistically different. p=0.05 The oligo I (SEQ. ID NO:1), an anti-adenosine A, receptor oligo, acts specifically on the adenosine A, receptor, but not on the adenosine A 2 receptors. These results stem from the treatment of rabbits with anti-sense oligo I (SEQ. ID NO.1) or mismatch control oligo (SEQ. ID NO:2431; AMM2) as described in Example 9 above and in Nyce Metzger (1997), supra (four doses of 5 mg spaced 8 to 12 hours apart via nebulizer via endotracheal tube), bronchial smooth muscle tissue excised and the number of adenosine A, and adenosine A 2 receptors determined as reported in Nyce Metzger (1997), supra.

Example 22: Specificity of Oligo I (SEQ. ID NO:1) for Target Gene Product Oligo I (SEQ. ID No:1) is specific for the adenosine AI receptor whereas its mismatch controls had no activity. Figure 1 depicts the results obtained from the cross-over experiment described in Example above and in Nyce Metzger (1997), supra. The two mismatch controls (SEQ. ID NO:2431 and SEQ. ID NO:2432) evidenced no effect on the PC 50 Adenosine value. On the contrary, the administration of anti-sense S 25 oligo I (SEQ. ID NO:1) showed a seven-fold increase in the PC 50 Adenosine value. The results clearly indicate that the anti-sense oligo I (SEQ. ID NO: 1) reduces the response (attenuates the sensitivity) to exogenously administered adenosine when compared with a saline control. The results provided in Table 2 above clearly establish that the effect of the anti-sense oligo I is dose dependent (see, column 3 of Table The Oligo I was also shown to be totally specific for the adenosine A, receptor, (see, top 3 rows of Table inducing no 30 activity at either the closely related adenosine A 2 receptor or the bradykinin B 2 receptor (see, lines 8-10 of Table 2 above). In addition, the results shown in Table 2 establish that the anti-sense oligo I (SEQ. ID *0* H:\Gabrila\Keep\Spec9395 -98.doc 05/07/02 NO:1) decreases sensitivity to adenosine in a dose dependent manner, and that it does this in an anti-sense oligo-dependent manner since neither of two mismatch control oligonucleotides (AiMM2; SEQ. ID NO:2431 and AIMM3; SEQ. ID NO:2432) show any effect on PC50 Adenosine values or on attenuating the number of adenosine Ai receptors.

Example 23: Effect on Aeroallergen-induced Bronchoconstriction Inflammation The Oligo I (SEQ. ID NO:1) was shown to significantly reduce the histamine-induced effect in the rabbit model when compared to the mismatch oligos. The effect of the anti-sense Oligo I (SEQ. ID No:1) and the mismatch oligos (AIMM2, SEQ. ID NO:2431 and AIMM3, SEQ. ID NO:2432) on allergen-induced airway obstruction and bronchial hyperresponsiveness was assessed in allergic rabbits. The effect of the antisense oligo I (SEQ. ID NO:1) on allergen-induced airway obstruction was assessed. As calculated from the area under the plotted curve, the anti-sense oligo I significantly inhibited allergen-induced airway obstruction when compared with the mismatched control p<0.05; repeated measures ANOVA, and Tukey=s t test). A complete lack of effect was induced by the mismatch oligo AIMM2 (Control) on allergen induced airway obstruction. The effect of the anti-sense oligo I (SEQ. ID NO:1) on allergen-induced BHR was determined as above. As calculated from the PCso Histamine value the anti-sense oligo I (SEQ. ID NO:1) significantly inhibited allergen-induced BHR in allergic rabbits when compared to the mismatched control p<0.05; repeated measures ANOVA, Tukey=s t test). A complete lack of effect of the AIMM mismatch control on allergen-induced BHR was observed. The results indicated that anti-sense oligo I (SEQ.

ID NO: 1) is effective to protect against aeroallergen-induced bronchoconstriction (house dust mite). In addition, the anti-sense oligo I (SEQ. ID NO:1) was also found to be a potent inhibitor of dust mite-induced bronchial hyper responsiveness, as shown by its effects upon histamine sensitivity which indicates antiinflammatory activity for anti-sense oligo I (SEQ. ID NO:1).

Example 24: Anti-sense Oligo I is Free 25 of Deleterious Side Effects S: The Oligo I (SEQ. ID NO:1) was shown to be free of side effects that might be toxic to the recipient. No changes in arterial blood pressure, cardiac output, stroke volume, heart rate, total peripheral resistance or heart contractility (dPdT) were observed following administration of 2.0 or 20 mg oligo I (SEQ. ID NO:1). The addition, the results of the measurement of H:\Gabriela\Keep\Spcc\93951-98.doc 05/07/02 WO 99/13886 PCT/US98/19419 cardiac output stroke volume mean arterial pressure (MAP), heart rate total peripheral resistance (TPR), and contractility (dPdT) with a Cardiomaxm apparatus (Columbus Instruments, Ohio) were assessed.

These results evidenced that oligo I (SEQ. ID NO:1) has no detrimental effect upon critical cardiovascular parameters. More particularly, this oligo does not cause hypotension.

This finding is of particular importance because other phosphorothioate anti-sense oligonucleotides have been shown in the past to induce hypotension in some model systems.

Furthermore, the adenosine A, receptor plays an important role in sinoatrial conduction within the heart. Attenuation of the adenosine A, receptor by anti-sense oligo I (SEQ. ID NO:1) might be expected to result, therefore, in deleterious extrapulmonary activity in response to the downregulation of the receptor. This is not the case. The anti-sense oligo I (SEQ. ID NO:1) does not produce any deleterious intrapulmonary effects and renders the administration of the low doses of the present anti-sense oligo free of unexpected, undesirable side effects.

This demonstrates that when oligo I (SEQ. ID NO:1) is administered directly to the lung, it does not reach the heart in significant quantities to cause deleterious effects. This is in contrast to traditional adenosine receptor antagonists like theophylline which do escape the lung and can cause deleterious, even life-threatening effects outside the lung.

Example 25: Long Lasting Effect of Oligo I The Oligo I (SEQ. ID NO:1) evidenced a long lasting effect as evidenced by the PCo and Resistance values obtained upon its administration prior to adenosine challenge.

The duration of the effect was measured for with respect to the PCo of adenosine antisense oligo I when administered in four equal doses of 5 mg each by means of a nebulizer via an endotracheal tube, as described above. The effect of the agent is significant over days 1 to 8 after administration. When the effect of the anti-sense oligo I (SEQ. ID NO:1) had disappeared, the animals were administered saline aerosols (controls), and the PC 50 Adenosine values for all animals were measured again. Saline-treated animals showed base line PC 5 o adenosine values The duration of the effect (with respect to Resistance) was measured for six allergic rabbits which were administered 20 mg of anti-sense oligo I (SEQ. ID NO: 1) as described above, upon airway resistance measured as also described above. The mean calculated duration of effect was 8.3 days for both PQo adenosine (p <0.05) and resistance (p <0.05).

These results show that anti-sense oligo I (SEQ. ID NO:1) has an extremely long duration of action, which is completely unexpected.

Example 26: Anti-sense Oligo II S105 WO 99/13886 PCT/US98/19419 Anti-sense oligo II, targeted to a different region of the adenosine A, receptor mRNA, was found to be highly active against the adenosine A,-mediated effects. The experiment measured the effect of the administration of anti-sense oligo II (SEQ. ID NO:7) upon compliance and resistance values when 20 mg anti-sense oligo II or saline (control) were administered to two groups of allergic rabbits as described above. Compliance and resistance values were measured following an administration of adenosine or saline as described above in Example 13. The effect of the anti-sense oligo of the invention was different from the control in a statistically significant manner, p<0.05 using paired t-test, compliance; p<0.01 for resistance.

The results showed that anti-sense oligo II (SEQ. ID NO:7), which targets the adenosine A, receptor, effectively maintains compliance and reduces resistance upon adenosine challenge.

Example 27: Antisense Oligos III and IV Oligos III (SEQ. ID NO:8) and IV (SEQ. ID NO:9) were shown to be in fact specifically targeted to the adenosine A 3 receptor by their effect on reducing inflammation and the number of inflammatory cells present upon separate administration of 20 mg of the anti-sense oligos III (SEQ. ID NO:8) and IV (SEQ. ID NO:9) to allergic rabbits as described above. The number of inflammatory cells was determined in their bronchial lavage fluid 3 hours later by counting at least 100 viable cells per lavage.

The effect of anti-sense oligos III (SEQ. ID NO:8) and IV (SEQ. ID NO:9) upon granulocytes, and upon total cells in bronchial lavage were assessed following exposure to dust mite allergen. The results showed that the anti-sense oligo IV (SEQ. ID NO:9) and antisense oligo III (SEQ. ID NO:8) are very potent anti-inflammatory agents in the asthmatic lung following exposure to dust mite allergen. As is known in the art, granulocytes, especially eosinophils, are the primary inflammatory cells of asthma, and the administration of anti-sense oligos III (SEQ. ID NO:8) and IV (SEQ. ID NO:9) reduced their numbers by 40% and 66%, respectively. Furthermore, anti-sense oligos IV (SEQ. ID NO:9) and III (SEQ. ID NO:8) also reduced the total number of cells in the bronchial lavage fluid by 40% and 80%, respectively.

This is also an important indicator of anti-inflammatory activity by the present anti-adenosine

A

3 agents of the invention. Inflammation is known to underlie bronchial hyperresponsiveness and allergen-induced bronchoconstriction in asthma. Both anti-sense oligonucleotides III (SEQ.

ID NO:8) and IV (SEQ. ID NO:9), which are targeted to the adenosine A 3 receptor, are representative of an important new class of anti-inflammatory agents which may be designed to specifically target the lung receptors of each species.

Example 28: Anti-sense Oligo V The anti-sense oligo V (SEQ. ID NO:10) targeted to the adenosine Ab adenosine receptor mRNA was shown to be highly effective at countering adenosine A-mediated effects and at reducing the number of adenosine A2b receptors present to less than half.

Example 29: Unexpected Superiority of Substituted over Phosphodiester-residue Oligo I-DS (SEQ. ID NO:1) Oligos I (SEQ. ID NO:1) and I-DS (SEQ. ID NO:1) were separately administered to allergic rabbits as described above, and the rabbits were then challenged with adenosine. The phosphodiester oligo I-DS (SEQ. ID NO:1) was statistically significantly less effective in countering the effect of adenosine whereas oligo I (SEQ. ID NO:1) showed high effectiveness, evidencing a PC 5 o Adenosine of 20 mg.

Example 30: Anti-sense Oligo VI For the present work, I designed an additional anti-sense phosphorothioate oligo targeted to the adenosine Al receptor (Oligo VI). This anti-sense oligo was designed for therapy on a selected species as described in the above patent application and is generally specific for that species, unless the segment of the adenosine receptor mRNA of other species elected happens to have a similar sequence. The anti-sense oligos were prepared as described below, and tested in vivo in a rabbit model for bronchoconstriction, inflammation and lung allergy, which have breathing difficulties and impeded lung airways, as is the case in ailments such as asthma, as described in the above-identified application. One additional oligo and its effect in a rabbit model was studied and the results of the study are reported and discussed below. The present oligo (antisense oligo VI) was selected for this study to complement the data on SEQ ID NO: 1 (Oligo which is antisense to the adenosine A, receptor mRNA provided in the above-identified patent application. This additional oligo is identified as anti-sense Oligo VI, and is targeted to a different region of the adenosine A, receptor mRNA than Oligo I. The design and synthesis of this anti-sense oligo was performed in accordance with the teaching, particularly Example 1, of the above-identified patent application. The anti-sense Oligo VI is a phosphorothioate designed to target the coding region of the rabbit adenosine A, receptor mRNA region +964 to +984 relative to the initiation codon (start site). The Oligo VI was prepared as described in the 25 above-indicated application, and is 20 nucleotides long. The OligoVI is directed to the adenosine A 1 receptor gene, and has the following sequence: 5'-CGC CGG CGG GTG CGG GCC GG-3' (SEQ. ID NO:2433).

The phosphorothioate anti-sense Oligo VI having the sequence described in above, was synthesized on an Applied Biosystems Model 396 Oligonucleotide Synthesizer, and purified using NENSORB chromatography S: (DuPont, DE). TETD (tetraethylthiuram disulfide) was used as the sulfurizing agent during the synthesis.

Example 31: Preparation of Allergic Rabbits Neonatal New Zealand white Pasturella-free rabbits were immunized intraperitoneally within 24 hours of birth with 0.5 ml of 312 antigen units/ml house dust mite farinae) extract (Berkeley Biologicals, Berkeley, CA) mixed with 10% kaolin as previously described (Metzger, W. in Late Phase Allergic V Reactions, Dorsch, Ed., CRC Handbook, pp 347-362, CRC Press, Boca Raton, 0 *00* H:\Gabriela\Kcep\Speci\93951-98.doc 05/07/02 ^v2\i WO 99/13886 PCT/US98/19419 1990; Ali, S. Et al., Am. J. Resp. Crit. Care Med. 149: 908 (1994)).

The immunizations were repeated weekly for the first month and then bi-weekly until the animals were 4 months old. These rabbits preferentially produce allergen-specific IgE antibody, typically respond to aeroallergen challenge with both an early and late-phase asthmatic response, and show bronchial hyper responsiveness (BHR). Monthly intraperitoneal administration of allergen (312 units dust mite allergen, as above) continues to stimulate and maintain allergen-specific IgE antibody and BHR. At 4 months of age, sensitized rabbits were prepared for aerosol administration as described by Ali et al. (1994), supra.

Example 32: Adenosine Aerosol Preparation An adenosine aerosol (20 mg/ml) was prepared with an ultrasonic nebulizer (Model 646, DeVilbiss, Somerset, PA), which produced aerosol droplets, 80% of which were smaller than 5pm in diameter. Equal volumes of the aerosols were administered directly to the lungs via an intratracheal tube to all three rabbits.

The animals were then administered the aerosolized adenosine and Day 1 pre-treatment values for sensitivity to adenosine were calculated as the dose of adenosine causing a 50% loss of compliance (PCo Adenosine). The animals were then administered the aerosolized anti-sense via the intratracheal tube (5 mg/1.0 ml), for 2 minutes, twice daily for 2 days (total dose, 20 mg). Post-treatment

PC

5 0 values were recorded (post-treatment challenge) on the morning of the third day. The results of these studies are provided in below.

Example 33: Anti-sense Oligo Formulation Each one of anti-sense oligos were separately solubilized in an aqueous solution and administered as described for anti-sense oligo I in above, in four 5 mg aliquots (20 mg total dose) by means of a nebulizer via endotracheal tube, as described above.

Example 34: Oligo VI Reduces Response to Adenosine Challenge as well or Better than Oligo I Oligo VI was tested in three allergic rabbits of the characteristics and readied as described in (7) above and in the above-indicated patent application. Oligo VI targets a section of the coding region of the A, receptor which is different from Oligo I. Both these target sequences were selected randomly from many possible coding region target sequences.

The three rabbits were treated identically as previously indicated for Oligo I. Briefly, 5 mg of Oligo VI were nebulized to the rabbits twice per day at 8 hour intervals, for two days. Thereafter, PCs adenosine studies were performed on the morning of the third day and compared to pre-treatment PCo values. This protocol is described in more detail in Nyce and Metzger (Nyce Metzger, Nature 385: 721- 725 (1997)).

The results obtained for the three rabbits are shown in Table 1 below.

Table. 1: PCo Adenosine before after Aerosolized Adenosine Treatment reatment Time PC 5 o Adenosine (mg) WO 99/13886 PCTIUS98/19419 Pre-treatment 3.0 ±2.1 Post-treatment >20.0* maximum achievable dose due to adenosine insolubility in saline All three animals treated with Oligo VI completely eliminated sensitivity to adenosine up to the measurable level of the agent shown in Table 1 above. That is, the administration of the Oligo VI abrogated the adenosine-induced bronchoconstriction in the three allergic rabbits. The actual efficacy of Oligo VI is, therefore, greater than could be measured in the experimental system used.

By comparing with the previously submitted results for the Oligo I, it may be seen that the Oligo VI was found to be as effective, or more, than Oligo I.

Example 34: Conclusions The work described and results discussed in the examples clearly indicates that all antisense oligonucleotides designed in accordance with the teachings of the above-identified application were found to be highly effective at countering or reducing effects mediated by the receptors they are targeted to. That is, each and all of the two anti-sense oligos targeting an adenosine A, receptor mRNA, 1 anti-sense oligo targeting an adenosine A 2 b receptor mRNA, and the 2 anti-sense oligos targeting an A 3 receptor mRNA were shown capable of countering the effect of exogenously administered adenosine which is mediated by the specific receptor they are targeted to.

The activity of the anti-sense oligos of this invention, moreover, is specific to the target and substitutively fails to inhibit another target.

In addition, the results presented also show that the administration of the present agents results in extremely low or non-existent deleterious side effects or toxicity.

This represents 100% success in providing agents that are highly effective and specific in the treatment of bronchoconstriction and/or inflammation. This invention is broadly applicable in the same manner to all gene(s) and corresponding mRNAs encoding proteins involved in or associated with airway diseases.

A comparison of the phosphodiester and a version of the same oligonucleotide wherein the phosphodiester bonds are substituted with phosphorothioate bonds evidenced an unexpected superiority for the phosphothiorate oligonucleotide over the phosphodiester anti-sense oligo.

The foregoing examples are illustrative of the present invention, and are not to be construed as limiting thereof. The invention is defined by the following claims, with equivalents of the claims to be included therein.

Claims (21)

1. An agent, comprising an oligonucleotide (oligo) that is anti-sense to a segment of at least two nucleic acid targets, wherein the oligo(s) is at least 60% horologous to a segment of the at least two target genes, coding or non-coding regions of RNAs corresponding to the target genes, the genes' initiation codons, genomic flanking regions, intron-exon borders, their 5'-end, 3' end, or regions within 2 to 10 nucleotides of the 5'-end or the 3'-end, the juxta-section between coding or non-coding regions, or all RNA segments encoding proteins associated with one or nore disease or condition(s)

2. An agent according to claim 1, whezein at least one target encodes a transcription factor, stimulating or activating factor, interleukin, interleukin receptor, chemokine, chemokine receptor, endogenously produced specific or non-specific enzyme, imrnunoglobulin, antibody receptor, central nervous system (CNS) or peripheral nervous or non-nervous system receptor, CNS or peripheral nervous or non-nervous system peptide transmitter, adhesion 20 molecule, defensine, growth factor, vasoactive peptide or receptor, or binding protein, or corresponds to an oncogene.

3. An agent according to claim 2, wherein the encoded receptors or peptide transmitters comprise synpathamnimetic receptors, parasympathetic receptors, GABA receptors, adenosine receptors, bradykinin receptors, insulin receptors, glucagon receptors, prostaglandin receptors, thyroid receptors, androgen receptors, anabolic receptors, estrogen receptors, progesterone receptors, receptors associated with the coagulation cascade, adenohypophyseal receptors, adenohypophyseal peptide transmitters, and histamine receptors (HisR).

4. An agent according to claim 3, wherein the encoded sympathamimetic receptors or parasympathomiretic receptors comprise acetylcholinesterase receptors (AcChaseR) acetylcholine receptors (AcChR), atropine receptors, muscarinic receptors, epinephrine receptors (EpiR), dopamine receptors (DOPAR), tachychinnen receptors, or norepinephrine receptors (NEpiR). An agent according to claim 2, wherein the encoded \\meb_E ilec\homs\Mancv~xeep~npsqi \395s1 .98 doq 26/0/02 26/04 2002 16:51 FAX 61 3 92438333 GRIFFITH RACK lih 00 ill enzymes ocrprise synthetased, kinases, crxidases, phosphatases, reductases, polysaccharide triglyceride, and protein hydrulases, esterases, elastases, or polysaccbaride, triglyceride, lipid or protein synthases-

6. An agent accordi to claim 5, wherein the encoded enzymes comprise tryptase, inducible nitric oxide synthase, cyclocxygenase (Ccx), MAP kinase, eosinophil peroxidase, P2- adrenergic receptor kinase, leukotriee c-4 syntbase, lipoxygenase, phosphodiesterase IV, metalloproteinase, CSBP/p38 MAP kinase, neutrophil elastasel phospholipase A2, cycloOxygenase 2 fucosyl transferas, IiB kinase 1 or 2, chymase, protein kinase C, thymidylate synthetase, tryptase, dihydrofolate re&.ictase, tryptase, thymidine kinase, deoxycytidine kinase, or ribonucleotide reductase.

7. An agent according to claim 2, wherein the encoded fUctor comprises NfcB transcriptioih. factor, granulocyte nacrophage colony stinujlating factor (CM-CSF) AP-1 transcription factor, nunocyte activatig factor, neutrophil chentactic factor, granlocyte colony-stirrulating- factor NEAT transcription factors, platelet activating factor, tumoa necrosis factor a (NP o, or a basic fibroblast growth factor (BFGF).

8. An agent accoring to claim 2, wherein the encoded adhesion rrlecule caomprises the intracellular adhesion molecules 1 (lCA-1), 2(ICAM-2) or 3 (ICAM-3), vascular cellular adhesion molecule (VCAM), endothelial leukocyte adhesion mtlecule-l (ELAM-), GATA transcription factor, neutrophil adherence receptor, or wad. CAM-i.I

9. An agent accordi to claim 2, wherein the encoded cytokines, lrphokines and cbemnkines camprise interleukin-1 (II-1), (IL-1p), inti rleukin-3 interleukin-4 (IL-4), inte eukin-8 interleukin-9 (IL-9), interleukin- 11 (IL-fl), CCR-5 CC cherokine, or Rantes. An agent according to claim 2, wherein the encoded receptor comprises adenosixt A 1 receptor, adenosine A- receptor, adenosine A 2 receptor, endothelin receptor A, eniothelin receptor B, lyE receptors, nuscarinic aetylcholine receptors, substance P receptor, histamine receptpr, CCR-1 CC chemokine receptor, subst.ance \\rlb t ilenhobms \%nano\Keep\Sqe Ci\93951.9 .ddoe 26104,02 26/04 2002 16:52 FAX 61 3 92438333 GRIFFITH HACK [a009 112 P, NK-1, and NK-3 receptors, CCR-2 CC chemokine receptor, CCR-3 clC chnmkine receptor (Eotaxin Receptor), interleukin-1p receptor (iL- 1PR), interleukin-1 receptor interleukin-10 receptor (Ii- 1PR), interleukin-3 receptor (IL-3R), CCR-4 cc ChemTkine receptor, cysteinyl leuktriene receptors, prostanoid receptors, interleukin-1 receptor (IL-1R), interleukin-4 receptor (IL-4R), receptor (IL-5R), interleukin-8 receptor interleukin-9 receptor (IL-9R) interleukin-11 receptor (IL-11R), bradykinin B2 receptor, synpathomimetic receptors, parasympathamimetic receptors, GABA receptors, adenosine receptors, bradykinin receptors, insulin receptors, glucagon receptors, prostaglandin receptors, thyroid receptors, androgen receptors, anabolic receptors, estrogen receptors, progesterone receptors, receptors associated with the coagulation cascade, adenohypophyseal receptors, or histamine receptors (HisR).

11. An agent according to claim 2, wherein the encoded protein crprises eotaxin, major basic protein, preproendothelin, eosinophil cationic protein, P-selectin, STAT 4, STAT 6, c-mas, NF- Interleukin-6 (NF-IL-6), MIP-la, MCP-2, MCP-3, MCP-4, cyclophillins, PDG32 cyclosporin A-binding protein, FK5-binding protein, fibronectin, LFA-1 (CDlla/CD18), PECAM-1, C3bi, PSGL-1, CD-34, substance P, p150, 95, Mac-i (CD11b/CD18), VLA-4, CD18/CD11a, CD11b/CD18, C5a, CCR1, CCR2, CCR4, CCR5, or LTB-4.

12. An agent according to claim 2, wherein the encoded defensin comprises defensin 1, defensin 2, or defensin 3.

13. An agent according to claim 2, wherein the encoded selectin comprises ca4pl selectin, a457 selectin, LFA-1 selectin, E- selectin, P-selectin, or L-selectin.

14. An agent according to claim 2, wherein the mREA corresponds to an oncogene selected from ras, src, myc, or bcl-2. An agent according to any ane of claims 1 to 14, wherein at least one mononucleotide or linking phosphodiester residue of the anti-sense oligonucleotide(s) is substituted by a residue selected from the group consisting of methylphosponate, phosphotriester, phosphorothioate, phosphorodithioate, boranophosphate, formaetal, thioformacetal, thioether, carbonate, carbamate, sulfate, su.lfanate, sulfamate, sulfonamide, sulfone, sulfite, sulfaxide, sulfide, \\mebE f1cg\ho=Vmrancs\K eep\Spee1\ S1. .9 doe 26/04,02 V_ C "S. 26/04 2002 16:52 FAX 61 3 92438333 GRIFFITH HACK 01oio -113 hydroxylamine, methylene (uethyimino), nthylenecay (rmthylimino), 2 O-rethyl, phosphoramidate residues, or cabinations thereof.

16. An agent according to claim 15, wherein substantially all residues are substituted.

17. An agent according to any one of claims 1 to 16, wherein the anti-sense oligonucleotide comprises about 7 to mononucleotides.

18. An agent according to any one of clairms 1 to 17, wherein the oligo consists of up to an including about 15% A.

19. An agent according to any one of claims 1 to 17, wherein the oligo is adenosine-free. An agent according to any one of claims 1 to 19, wherein the anti-sense oligo caromprises one or wore of SQ ID IoS.:1 through 93, or fragments thereof at least 7 and up to 60 nucleotides lcng.

21. An agent according to claim 1, wherein when the two target segrments have different bases in at least one site, the base in the corresponding site of the anti-sense oligo is substituted with a universal base selected from heteroaromatic bases which bind to both bases present in the targets' site.

22. An agent according to claim 21, wherein the heteroaraoratic bases carprise pyrimidines or purines, that may be substituted by OH, halo, NH 2 SH, SO, S0, SO 3 0OH or branched or fused primary or secondary amino, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, alkenoxy, acyl, cycloacyl, azylacyl, alkynxy, cycloalkoxy, aroyl, arylthio, arylsulfoxyl, halocycloalkyl, alkylcycloalkyl, alkenylcycloalkyl, alkynylcycloalkyl, haloazyl, alkylaryl, alkenylaryl, alkynylatyl, azylalkyl, azylalkenyl, azylalkynyl, arylcycloalkyl, which mray be further substituted by OH, halo, NH 2 primary, secondary or tert Lazy amine, SH, SO, S02, SO 3 cycloalkyl, heterocycloalkyl or heteroatyl.

23. An agent according to claim 22, wherein the pyrimidines are substituted at positions 2, 3, 4, 5 and/or 6 and the purines are substituted at positions 1, 2, 3, 6 and/or 8.

24. An agent according to claim 23, wherein the pyrimidines or purines have the chemnical fornrula \\mlbEgi\hameS\MMOaa\ lep\speci\ 9 3

951.8 .dac 26/04.02 26/04 2002 16:52 FAX 61 3 92438333 GRIFFITH HACK [oii 114 O H II I I 5O7\a r R2 wherein R and R 2 are independently H, alkyl, alkenyl or alkynyl and R is H, azyl, dicycloalkyl, dicycloalkenyl, dicycloalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, 0- cycloalkyl, O-cycloalkenyl, O-cycloalkynyl, NM -alkylamino- ketoxyalkyloxy-aryl and trno and dialkylaminnoalkyl-N-alkylamino- 0 aryl. An agent according to claim 24, wherein the pyrimidines or purines corprise theophylline, caffeine, dyphylline, etaphylline, acephylline piperazine, barmifylline, enprofylline or xanthine. 26, An agent according to claim 25 wherein the universal base caprises 3-nitropyrrole-2' -deaxynucleoside, 5-nitro-indole, 2- deoxyribosyl- (5-nitroindole), 2-deaxyribofuranosyl- (5-nitroindle) 2 -deoxyinosine, 2' -deoxynebularine, GH,- RH-3,4-dihydropyrimido 20 oxazine-7-one and 2-amino-6-methoxyaminopurine. 27. An agent according to any one of claims 1 to 26, where a mrethylated cytocine is substituted for at least one CG dinucleotide if present in the oligo(s). 28. An agent according to any one of claims 1 to 26, wherein the agent's adenosine base(s) are substituted with a universal base selected from heteroazonatic bases that bind to the base(s) present in the targets' site and have adenosine receptor antagonist *..activity or less than about 0.3 of the adenosine agonist activity at the adenosine A, Ab and/or A 3 receptors, or hetercaramtic bases which have no activity or have agonist activity at the adenosine A2 receptor. 29. An agent accordin to any one of claims 1 to 28, wherein the anti-sense oliganucletide is operatively linked to a eukaryotic or prokaryotic vector, or to a cell internalized or up-taken agent, which is optionally selected focm transferrin, asialogylcoprotein, SO, or streptavidin. 1 30. A composition, corrprising the agent: according to any one \\melbbfilee\bcw42\nz\Xee\S g*i\93P1.B .dC 6/04 02 26/04 2002 16:53 FAX 61 3 92438333 GRIFFITH HACK 11012 115 of claims 1 to 29 and a pharmaceutically or veterinarily acceptable carrier. 31. A caomposition according to claim 30, wherein the carrier is selected from gaseous, liquid or solid carriers. 32. A composition according to claim 30 or claim 31, further corprising other therapeutic caipounds, surfactants, antioxidants, flavouring or coloring agents, fillers, volatile oils, buffering agents, dispersants, RNA inactivating agents, antioxidants, flavouring agents, propellants or preservatives. 33. A composition according to any one of claims 30 to 32, wherein the anti-sense oligonucleotide is present in an armount of about 0.01 to about 99.99 w/w of the composition. 34. A caomposition according to claim 33, comprising the nucleic acid, a surfactant and a carrier. 15 35. A composition according to claim 34, wherein the surfactant is selected from the group consisting of surfactant S.protein A, surfactant protein B, surfactant protein C, surfactant protein D, surfactant protein E or active fragmrents thereof, non- dipalmitayl disaturated phosphatidylcholine, 20 dipalmitoylphosphatidylcholine, phosphatidylcholine, phosphatidylglycerol, phosphatidylinositol, phosphatidyletbanolamine, phosphatidylserine, phosphatidic acid, 0 ubiguinones, lysophosphatidylethanolamine, lysophosphatidylcholine, palmitoyl-lysophosphatidylcholine, dehyroepiandrosterne, dolicols, sulfatidic acid, glycerol-3-phosphate, dihydroxyacetone phosphat e, glycerol, glycero-3-phosphocholine, dihydroxyacetone, palirntate, cytidine diphosphate (CDP) diacylglycerol, CDP choline, choline, choline phosphate, artificial lamellar bodies vehicles for surfactant caomponents, omega-3 fatty acids, polyenic acid, polyenoic acid, lecithin, palmitic acid, non-ionic ethylene and/or propylene oxide block copolyrmers, polyaxypropylene, polyoxyethylene, poly (vinyl amine) with dextran and/or alkanoyl side chains, Brij Triton X-100, ALEC, Exosurf, Survant or Atavaquane. 36. A formulation, comprising a coposition according to any one of claims 30 to 35, wherein the carrier colaprises a hydrophcbic carrier. 37. A formulation according to claim 36, wherein the carrier 39 doc 26/04j02 26/04 2002 16:53 FAX 61 3 92438333 GRIFFITH HACK [1013 116 comprises lipid particles or vesicles. 38. A formulation according to claim 37 wherein the vesicles comprise liposomes and particles comprise micro crystals. 39. A formulation according to claim 37, wherein the lipid vesicles comprise 2, 3-dioleoxylxi] propyl) N, N- trimethyl- ammonium methylsulfate. A formulation according to any one of claims 36 to 39, comprising a respirable formulation. 41. A formulation according to any one of claims 36 to 39, comprising an aerosol. 42. A formulation according to any one of claims 36 to 39, in a single or multiple unit form. 43. A formulation according to any one of claims 36 to 39, in bulk. 15 44. A formulation according to any one of claims 36 to 39, which comprises a nasal formulation of particle :size 10 to 500 t. 45. A formulation according to any one of claims 36 S: to 39, which is a respirable or inhalable formulation 20 comprising a solid powdered or liquid aerosol or spray of particle size about 0.5 g to 10 g. 46. A formulation according to any one of claims 36 to 39, wherein the formualtion is administered in vitro, orally, intracavitarily, intranasally, intraanally, 25 intravaginally, intrauterally, intrachranially, pulmonarily, intrarenally, intranodularly, intraarticularly, intraotically, intralymphatically, tranadermally, intrabucally, intravenously, subcutaneously, intramuscularly, intratumorously, intraglandularly, intraocularly, intracranial, into an organ, intravascularly, intrathecally, by implantation, by inhalation, intradermally, intrapulmonarily, into the ear, into the heart, by slow release, by sustained release or by a pump. 47. A capsule or cartridge, comprising the composition o:r: formulation of any one of claims 30 to S" 48. A kit comprising a delivery device, in a separate \\\merl Ciluef\hcmet\Mnac8B\Kp\Bpeciil93951.p oc 326/04/02 26/04 2002 16:53 FAX 61 3 92438333 GRIFFITH HACK la014 117 container, the caPposition or forallation according to any one of claims 30 to 35 and instructions for its use. 49. A kit according to claim 48, wherein the delivery device comprises a nebulizer that delivers single metered doses of the forrulation. A kit according to claim 49, wherein the nebulizer corprises an insufflator, and the composition or formulation is provided in a piercable or openable capusle or cartridge. 51. A kit according to claim 48, wherein the delivery device comprises a pressurized inhaler, and the composition or formulat Loan comprises a suspension or solution of the agent. 52. A kit according to any one of claims 47 to 51, further comprising in a separate container an agent selected fromn other therapeutic compounds, surfactants, antioxidants, flavouring and coloring agents, fillers, volatile oils, buffering agents, dispersants, cell internalized or up taken agents, RNA inactivating agents, antioxidants, flavouring agents, propellants or preservatives. 53. A kit according to claim 52, wherein the surfactant 20 comrprises surfactant protein A, surfactant protein B, surfactant protein C, surfactant protein D, surfactant protein E or active fragmrrents thereof, non-dipalmitoyl disaturated phosphatidylcholine, dipalmitylphosphatidylcholine, phosphatidylcholine, phosphatidylglycerol, phosphatidylinositol, phosphatidylethanolamine, phosphatidylserine, phosphatidic acid, ubiquinones, lysophosphatidylethanolamine, lysophosphatidylcholine, S.palmitoyl-lysphosphatidylcholie, dehydroepiandrosterone, dolichols, sulfatidic acid, glycerol -3-phosphate, dihydraxyacetne phosphate, glycerol, glycero-3-phosphocholine, dihydrCacyaCetfne, palmitate, cytidine diphophate (CDP) diacylglycerol, CDP choline, choline, choline phosphate, artificial larrellar bodies vehicles for surfactant components, amega-3 fatty acids, polyenic acid, polycnoic acid, lecithin, palmitic acid, non-ionic ethylene and/or propylene oxide block copolymers, polyoxypropylene, polyaxyethylene, poly (vinyl amine) with dextran and/or alkanoyl side chains, Brij Triton X-100, ALEC, Bsurf, Survant or Atovaquone. S 54. A kit according to any one of claims 47 to 53, wherein \\inlabtiles\hr.um\Anaa\Seep\S6C1\93951.9 .doc26/04/02 26/04 2002 16:54 FAX 61 3 92438333 GRIFFITH HACK [1015 118 the conposition or formulation is provided in a capsule or cartridge. A cell, comprising the agent according to any one of claims 1 to 29. 56. A method of treating a disease or condition associated with levels of the mRNA(s) corresponding to at least one target gene(s), genomic flanking regions, or encoded proteins, ccaprising administering to a subject afflicted with the disease or condition the agent according to any one of claims 1 to 29, comprising an amount of the anti-sense oligonucleotide(s) (oligo(s)) effective to reduce the production or availability, or to increase the degradation by the subject of at least one of the target mRNA(s). 57. A method according to claim 56, wherein the agent is administered in an amount effective to reduce the production or availability, or to increase the degradation of at least two of the target mRNAs. 58. A method according to claim 56 or claim 57, wherein the agent is administered directly to the lung(s) of the subject. 59. A method according to claim 58, wherein the agent is 20 administered as a respirable aerosol. A method according to claim 56, which comprises a nasal formulation of particle size 10 p to 500 p. 61. A method according to claim 56, which is a respirable or inhalable formulation comprising a solid powdered or liquid aerosol or spray of particle size about *0.5 p to 10 p. 62. A method according to claim 56, wherein the agent is administered in vitro, orally, intracavitarily, S" intranasally, intraanally, intravaginally, intrauterally, intrachranially, pulmonarily, intrarenally, intranodularly, intraarticularly, intraotically, intralymphatically, transdermally, intrabucally, intravenously, subcutaneously, intramuscularly, intratumorously, intraglandularly, intraocularly, intracranial, into an organ, intravascularly, intrathecally, by implantation, by inhalation, intradermally, intrapulmonarily, into the ear, -into the heart, by slow release, by sustained release or by \\melbfille\hoeS\nnao\ccp\Bpcci\939s .s a .doc 2/04o 01 26/04 2002 16:54 FAX 61 3 92438333 GRIFFITH HACK @o016 119 a pump. 63. A method according to any one of claims 56 to 58, wherein the disease or condition is a lung disease or condition, and at least one of the target mRNA encodes a protein selected from adenosine A receptor, adenosine A& receptor, adenosine A 3 receptor, or bradykinin B2 receptor. 64. A method according to claim 63, wherein the disease or condition is associated with obstruction of the subject's airways. A method according to claim 64, wherein the disease or condition is associated with asthma. 66. A method according to any one of claims 56 to 65, wherein one of the target proteins comprises the NfKB transcription factor. 67. A method according to any one of claims 56 to 65, wherein the disease or condition is associated with inflamnation, and at least one of the target mRNA encodes a protein selected from interleukins, chemokines, Rantes or receptors thereof. 68. A method according to any one of claims 56 to 58, wherein the disease or condition is associated with an allergy, and the mRNA encodes a target selected from irrmmoglobulins or receptors. 20 69. A method according to any one of claims 56 to 64, wherein Sthe disease or condition is associated with a malignancy or cancer, and the mRNA encodes a target selected from oncogenes, inmnunoglobulins or antibody receptors. 70. A method according to any one of claims 56 to 69, wherein the composition is administered by a transdermal or systemic route. S71. A method according to claim 70, wherein the composition is administered orally, intracavitarily, intranasally, intraanally, intravaginally, transdermally, intrabucally, intravenously, i .subcutaneously, intramuscularly, intratumorously, intraglandulaly, introcularly, intracranial, into an organ, intravascularly, intrathecally, by implantation, by inhalation, intradermally, intrapulmcnarily, into the ear by slow release, by sustained re ease by a pump or intradermally. 72. A method according to any one of claims 56 to 71, wherein the subject is a vertebrate. 73. A method according to claim 72, wherein the subject is a R mammal. \\clhb_ile\ho f$\laoa\kxeep\Spil\S93S51 .SB.doc 26/04'02 26/04 2002 16:54 FAX 61 3 92438333 GRIFFITH HACK @1017 120 74. A method according to claim 73, wherein the mammal is a human, or a small or large, wild or domesticated, marine or farm animal. A method according to claim 73, wherein the mantals are human and domesticated or farm animals. 76. A method according to any one of claims 56 to 75, wherein at least one of the target mRNAs and the subject are of the samu species. 77. A method according to any one of claims 56 to 75, wherein at least one of the target mRNAs and the subject are human. 78. A method according to any one of claims 56 to 77, wherein the anti-sense oligonucleotide is administered in an amount of about 0.005 to about 150 mg/kg body weight. 79. A method according to claim 78, wherein the anti-sense oligonucleotide is administered in an armount of about 0.01 to alout 75 mg/kg body weight. 80 A method according to claim 79, wherein the anti-sense oligonuclectide is administered in an amount of about 1 to 50 mrT/kg body weight. 20 81. A method according to any one of claims 56 to 80, being a prophylactic method. 82. A method according to any one of claims 56 to 82, being a therapeutic method. \83. A method of producing a multiple target anti-sense oligonucleotide (oligo), comprising selecting two or more targets selected from genes, genomic flanking regions, RNA segments or proteins associated wi.th at least one disease or condition; obtaining RNA sequences corresponding to the genes or genomic flanking regions or RNAs encoding target proteins; selecting one or more segment of a first (sense) RNA sequence that is at least about 60% homologous to at least a serment of a second RNA sequence; and synthesizing one or more anti-sense oligo(s) to the ,ane or more RNA segment 84. A method according to claim 83, wherein the selected RNA sequences are at least 4 and up to 60 nucleotides long, and \\melbf_ilea\hame$\Anunae\Keep\Speei\93951-98-doC 26/04/02 26/04 2002 16:55 FAX 61 3 92438333 GRIFFITH HACK E1018 121 optionally comprise up to about 15% cytosine and guanidine A method according to claim 83, wherein the oligo(s) that is (are) anti-sense to the selected RNA sequence(s) are at least 4 and up to 60 nucleotides long, and optionally comprise up to about 15% cytosine and guanidine 86. A method according to any one of claims 83 to 85, further comprising substituting a universal base for at least one non- homologous nucleotide in the anti-sense oligonucleotide. 87. A method according to any one of claims 83 to 86, further comprising substituting a methylated cytosine for cytosine in al: least one CG dinucleotide present in the anti-sense oligonucleotide. 88. A method according to claim 87, wherein the anti-sense oligonucleotide(s) are about 7 to about 60 nucleotides long. 89. A method according to any one of claims 83 to 88, wherein the target proteins comprise transcription factors, stimulating or activating factors, interleukins, interleukin receptors, cherokines, chemokine receptors, endogenously produced specific or non-spec:.fic enzymes, imnunoglobulins, or receptors, central nervous systems (CNS) or peripheral nervous and non-nervous system receptors, CNS or 20 peripheral nervous or non-nervous system peptide transmitters, adhesion molecules, selectins, defensines, growth factors, vasoactive peptides, vasoactive peptide receptors, or binding proteins; or the RNA corresponds to an oncogene. 90. A method according to any one of claims 83 to 89, wherein the target genes are oncogenes. *91. A method according to any one of claims 83 to 90, wherein one or more selected RNA segment contain at least one thymidjne the method further comprises substituting in the anti-sense oligo at least one A corresponding to the T with a heteroaromatic base that comprises pyrimidines or purines, which may be substituted by CH, halo, NH 2 SH, SO, SOa, SOh, COOH or branched or fused primary or secondary amino, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, alkenxy, acyl, cycloacyl, arylacyl, alkynoxy, cycloalkoxy, aroyl, arylthio, arylsulfoxyl, halocycloalkyl, alkylcycloalkyl, alkenylcycloalky., alkynylcycloalkyl, haloaryl, alkylaryl, alkenylazyl, alkynylaryl, arylalkyl, arylalkenyl, arylalkynyl, arylcycloalkyl, which may be \\mel.b_Ei 1e9homelS\ACnan a\eep\Speci\93a1.9a.dnc 2S/04. 02 26/04 2002 16:55 FAX 61 3 92438333 GRIFFITH HACK a019 122 further substituted by OH, halo, NH 2 primary, secondary or terti azy amine, SH, SO, S, S03, cycloalkyl, heterocycloalkyl or heteroaryl. 92. A mrethod according to claim 91, wherein the pyrimidines are substituted at positions 2, 3, 4, 5 and/or 6 and purines are substituted at positions 1, 2, 3, 6 and/or 8. 93. A method according to claim 92, wherein the pyrimidines or purines are selected from those having the chemical faormula I 1 R0 N R2 wherein R 1 and R are independently H, alkyl, alkenyl or alkynyl and R 3 is H, azyl, dicycloalkyl, dicycloalkenyl, dicycloalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, 0- cycloalkyl, 0-cycloalkenyl, O-cycloalkynyl, N-alkylamino- ketoxyalkylcxy-aryl and mono and clialkylaminoalkyl -N-alkylamino-S aryl. 94. A method according to claim 93, wherein the pyrimidines or purines comprise theophylline, caffeine, dyphylline, etophylline, acephylline piperazine, bamifylline, enprofylline or xanthine. A method according to claim 93, wherein the universaL base comrprises 3-nitropyrrole-2' -deoxynucleoside, 5-nitro-indole, 2- deoxyribosyl- (5-nitroindole), 2-deoxyribofuranosyl- (5-nitroindol e), 2 '-dexyinosine, 2 '-decxynebularine, 6H, 8H-3,4-dihydropyrimido [4,5-cl oaxazine-7-one or 2-amino-6-rmathoxyaminpurine. 96. A method according to any one of claims 83 to 95, wherein the (sense) RNA sequence is used to search for (sense) RNA sequences of one or more secondary target(s) selected by their association with a pre-determined disease preferably related disease(s). 97. A method according to any one of claims 83 to 96, wherein the (sense) RNA sequence is used to search for (sense) RNA seque-nces of ane or rore secondary target by searching one of more sequence data bases. 98. A method according to any one of claims 83 to 95, wherein \\mellri2ea\home$\AnanaOc\C\peci\ 9 9 5A.9l .doc 36/ot, oa 26/04 2002 16:55 FAX 61 3 92438333 GRIFFITH HACK @020 123 one target is selected first and a search is undertaken for homologous sequences of specific targets, that are preferably associated with one or more related diseases. 99. A method according to any one of claims 83 to 95, wherein a primary target is selected first, and an anti-sense oligo sequence found, which is preferably an adenosine free (desA) oligo and, then, secondary, tertiary or more targets found by searching a polynucleotide data base. 100. A method according to any one of claims 83 to 95, wherein the selected targets are naturally homologous sequences. 101. An anti-sense oligonucleotide produced by the method according to any one of claims 83 to 94 and 96 to 100. 102. Use of an agent according to any one of claims 1 to 29 in the manufacture of a medicament used for treating a disease or condition associated with the mRNA corresponding to at least two target gene(s) genomic flanking regions, or proteins. 103. Use according to claim 102, wherein the agent is to he administered in an amount effective to reduce the production or availability, or to increase the degradation of at least two of the 20 target mRNAs. 104. Use according to claim 102 or claim 103, wherein the agent is administered directly to the lungs of a subject. 105. Use according to claim 102, which comprises a nasal formulation of particle size 10 g to 500 g. 106. Use according to claim 102, which is a respirable or inhalable formulation comprising a solid powdered or liquid aerosol or spray of particle size about 0.5 i to 107. Use according to claim 102, wherein the agent is administered in vitro, orally, intracavitarily, intranasally, intraanally, intravaginally, intrauterally, intrachranially, pulmonarily, intrarenally, intranodularly, intraarticularly, intraotically, intralymphatically, transdermally, intrabucally, intravenously, subcutaneously, intramuscularly, intratumorously, intraglandularly, intraocularly, intracranial, into an organ, Sintravascularly, intrathecally, by implantation, by \\mnlb_files\womi5\Ananos\eep\Speci\s3951.9 .ec 26e/D402 26/04 2002 16:56 FAX 61 3 92438333 GRIFFITH HACK 1021 124 inhalation, intradermally, intrapulmonarily, into the into the heart, by slow release, by sustained release a pump. ear, or by 108. A method according to claim 104, wherein the agent is administered as a respirable aerosol. 109. An agent according to claim 1 substantially as hereinbefore described with reference to any one of the exampleu. Dated this 26th day of April 2002 EAST CAROLINA. UNIVERSITY By their Patent Attorneys GRIFFITH HACK Fellows Institute of Patent and Trade Mark Attorneys of Australia ooeoo* S 0S@@ 0 e SoOO *O S t** S. 9e *S 0* \\melb ile\MqNtaS\nanoB\Keep\Speci\91s951.90- 0* 26/04 02