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NZ778442B2 - Transthyretin (TTR) iRNA compositions and methods of use thereof for treating or preventing TTR-associated diseases - Google Patents
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NZ778442B2 - Transthyretin (TTR) iRNA compositions and methods of use thereof for treating or preventing TTR-associated diseases - Google Patents

Transthyretin (TTR) iRNA compositions and methods of use thereof for treating or preventing TTR-associated diseases

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Publication number
NZ778442B2
NZ778442B2 NZ778442A NZ77844216A NZ778442B2 NZ 778442 B2 NZ778442 B2 NZ 778442B2 NZ 778442 A NZ778442 A NZ 778442A NZ 77844216 A NZ77844216 A NZ 77844216A NZ 778442 B2 NZ778442 B2 NZ 778442B2
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NZ
New Zealand
Prior art keywords
salt
rnai agent
double stranded
stranded rnai
seq
Prior art date
Application number
NZ778442A
Other versions
NZ778442A (en
Inventor
Amy Chan
Vasant Jadhav
Martin Maier
Kallanthottathil G Rajeev
Tracy Zimmermann
Original Assignee
Alnylam Pharmaceuticals Inc
Filing date
Publication date
Application filed by Alnylam Pharmaceuticals Inc filed Critical Alnylam Pharmaceuticals Inc
Publication of NZ778442A publication Critical patent/NZ778442A/en
Publication of NZ778442B2 publication Critical patent/NZ778442B2/en

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    • A—HUMAN NECESSITIES
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    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A61K31/713—Double-stranded nucleic acids or oligonucleotides
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
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    • A61P25/00—Drugs for disorders of the nervous system
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
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    • C12N2310/00—Structure or type of the nucleic acid
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    • C12N2310/00—Structure or type of the nucleic acid
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    • C12N2310/32—Chemical structure of the sugar
    • C12N2310/321—2'-O-R Modification
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    • C12N2310/00—Structure or type of the nucleic acid
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    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/30—Chemical structure
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    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/30—Chemical structure
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    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/30—Chemical structure
    • C12N2310/35—Nature of the modification
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    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
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    • C12Q2600/00—Oligonucleotides characterized by their use
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    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/178—Oligonucleotides characterized by their use miRNA, siRNA or ncRNA
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/46—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans from vertebrates
    • G01N2333/47—Assays involving proteins of known structure or function as defined in the subgroups
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/22—Haematology
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/28—Neurological disorders
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/28—Neurological disorders
    • G01N2800/2814—Dementia; Cognitive disorders
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/32—Cardiovascular disorders
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere

Abstract

The present invention provides iRNA agents, e.g., double stranded iRNA agents, that target the transthyretin (TTR) gene and methods of using such iRNA agents for treating or preventing TTR-associated diseases

Claims (34)

We claim:
1. A double stranded ribonucleic acid (RNAi) agent, or salt thereof, that inhibits sion of transthyretin (TTR) in a cell, comprising a sense strand ing by no more than 4 modified or unmodified tides from the nucleotide sequence 5'-usgsggauUfuCfAfUfguaaccaaga-3' of SEQ ID NO: 10 and an antisense strand differing by no more than 4 modified or unmodified nucleotides from the nucleotide sequence 5'-usCfsuugGfuuAfcaugAfaAfucccasusc-3' of SEQ ID NO: 7, wherein a, c, g, and u are 2'-O-methyl (2'-OMe) A, C, G, and U, respectively; Af, Cf, Gf, and Uf are 2'-fluoro A, C, G, and U, respectively; and s is a orothioate linkage.
2. The double stranded RNAi agent, or salt thereof, of claim 1, wherein the sense strand differs by no more than 3 modified or unmodified nucleotides from the nucleotide sequence 5'- usgsggauUfuCfAfUfguaaccaaga-3' of SEQ ID NO: 10 and the antisense strand differs by no more than 3 modified or fied nucleotides from the nucleotide sequence 5'- usCfsuugGfuuAfcaugAfaAfucccasusc-3' of SEQ ID NO: 7.
3. The double stranded RNAi agent, or salt thereof, of claim 1, wherein the sense strand differs by no more than 2 modified or unmodified nucleotides from the nucleotide sequence 5'- usgsggauUfuCfAfUfguaaccaaga-3' of SEQ ID NO: 10 and the antisense strand differs by no more than 2 ed or unmodified nucleotides from the nucleotide ce 5'- usCfsuugGfuuAfcaugAfaAfucccasusc-3' of SEQ ID NO: 7.
4. The double stranded RNAi agent, or salt thereof, of claim 1, wherein the sense strand differs by no more than 1 ed or unmodified nucleotide from the nucleotide sequence 5'- usgsggauUfuCfAfUfguaaccaaga-3' of SEQ ID NO: 10 and the antisense strand differs by no more than 1 modified or unmodified nucleotide from the nucleotide sequence 5'- usCfsuugGfuuAfcaugAfaAfucccasusc-3' of SEQ ID NO: 7.
5. The double stranded RNAi agent, or salt thereof, of claim 1, wherein the sense strand comprises the nucleotide sequence 5'-usgsggauUfuCfAfUfguaaccaaga-3' of SEQ ID NO: 10 and 21663224_1 (GHMatters) P107927.NZ.1 the antisense strand ses the nucleotide sequence 5'-usCfsuugGfuuAfcaugAfaAfucccasusc-3' of SEQ ID NO: 7.
6. The double stranded RNAi agent, or salt thereof, of claim 1, wherein the sense strand consists of the nucleotide sequence 5'-usgsggauUfuCfAfUfguaaccaaga-3' of SEQ ID NO: 10 and the antisense strand consists of the nucleotide sequence 5'-usCfsuugGfuuAfcaugAfaAfucccasusc- 3' of SEQ ID NO: 7.
7. The double stranded RNAi agent, or salt thereof, of any one of claims 1-6, further sing a .
8. The double stranded RNAi agent, or salt thereof, of any one of claims 1-6, wherein the sense strand is conjugated to a ligand.
9. The double stranded RNAi agent, or salt thereof, of claim 1, wherein the sense strand comprises the nucleotide sequence 5’- usgsggauUfuCfAfUfguaaccaaga – 3’ of SEQ ID NO: 10 and the antisense strand consists of the nucleotide sequence 5’- usCfsuugGfuuAfcaugAfaAfucccasusc – 3’ of SEQ ID NO: 7, n a, c, g, and u are 2'-O-methyl (2'-OMe) A, C, G, and U, respectively; Af, Cf, Gf, and Uf are 2'-fluoro A, C, G, and U, respectively; and s is a phosphorothioate linkage, and wherein the sense strand of the double ed RNAi agent is conjugated to a ligand.
10. The double stranded RNAi agent, or salt thereof, of claim 8 or 9, wherein the ligand is one or more GalNAc derivatives attached h a bivalent or trivalent branched linker.
11. The double stranded RNAi agent, or salt thereof, of claim 10, wherein the ligand is 21663224_1 (GHMatters) P107927.NZ.1 HO OH O H H HO O N N O HO OH O H H HO O N N O O O O HO OH HO O N N O AcHN H H O .
12. The double ed RNAi agent, or salt thereof, of claim 8 or 9, wherein the ligand is attached to the 3’ end of the sense .
13. The double stranded RNAi agent, or salt thereof, of claim 12, wherein the RNAi agent is conjugated to the ligand as shown in the following schematic , wherein X is O or S.
14. The double stranded RNAi agent, or salt thereof, of claim 13, wherein X is O.
15. The double stranded RNAi agent, or salt thereof, of claim 1, n the sense strand consists of the nucleotide sequence 5’- usgsggauUfuCfAfUfguaaccaaga – 3’ of SEQ ID NO: 10 and the antisense strand consists of the nucleotide sequence 5’- usCfsuugGfuuAfcaugAfaAfucccasusc – 3’ of SEQ ID NO: 7, wherein a, c, g, and u are 2'-O-methyl (2'-OMe) A, C, G, and U, respectively; Af, Cf, Gf, and Uf are 2'-fluoro A, C, G, and U, respectively; and s is a phosphorothioate linkage, and 21663224_1 (GHMatters) P107927.NZ.1 wherein the sense strand of the double stranded RNAi agent is conjugated to a ligand, as shown in the following schematic , wherein X is O.
16. A pharmaceutical composition comprising the double stranded RNAi agent, or salt thereof, of any one of claims 1-15.
17. The ceutical composition of claim 16, wherein double stranded RNAi agent, or salt thereof, is present in an unbuffered solution.
18. The pharmaceutical composition of claim 17, wherein the ered solution is saline or water.
19. The pharmaceutical composition of claim 16, wherein the double stranded RNAi agent, or salt thereof, is t in a buffer solution.
20. The pharmaceutical composition of claim 19, wherein the buffer solution comprises acetate, citrate, prolamine, carbonate, or phosphate or any combination thereof.
21. The pharmaceutical ition of claim 20, wherein the buffer solution is phosphate ed saline (PBS).
22. A method for inhibiting expression of transthyretin (TTR) in a cell in vitro, the method sing contacting the cell with the double stranded RNAi agent, or salt thereof, of any one of claims 1-15 or the pharmaceutical composition of any one of claims 16-21, thereby inhibiting expression of the TTR gene in the cell. 21663224_1 (GHMatters) P107927.NZ.1
23. The method of claim 22, wherein the TTR expression is inhibited by at least about 10%, about 15%, about 20%, about 25%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, about 98% or about 100%.
24. Use of the double stranded RNAi agent, or salt thereof, of any one of claims 1-15 or the pharmaceutical composition of any one of claims 16-21, for the manufacture of a medicament for treating a TTR-associated e in a subject.
25. The use of claim 24, wherein the medicament is ated to reduce, slow, or arrest a athy Impairment Score (NIS) or a modified NIS (mNIS+7) in the subject.
26. The use of claim 24, wherein the medicament is ated to increase a 6-minute walk test (6MWT) in the t.
27. The use of any one of claims 24-26, wherein the subject carries a TTR gene mutation that is ated with the development of a TTR-associated disease.
28. The use of any one of claims 24-26, wherein the TTR-associated disease is selected from the group consisting of senile systemic amyloidosis (SSA), systemic familial amyloidosis, familial amyloidotic polyneuropathy (FAP), familial dotic cardiomyopathy (FAC), leptomeningeal/Central Nervous System (CNS) amyloidosis, and hyperthyroxinemia.
29. The use of any one of claims 24-26, wherein the double stranded RNAi agent, or salt thereof, is to be administered to the subject by an administration means selected from the group ting of subcutaneous, intravenous, intramuscular, intrabronchial, intrapleural, intraperitoneal, intraarterial, lymphatic, cerebrospinal, and any combinations thereof.
30. The use of claim 29, wherein the double stranded RNAi agent, or salt thereof, is to be administered to the subject via subcutaneous, intramuscular or intravenous administration. 21663224_1 (GHMatters) P107927.NZ.1
31. The use of claim 30, wherein the double stranded RNAi agent, or salt thereof, is to be administered to the subject via subcutaneous administration.
32. The use of claim 31, wherein the subcutaneous administration is selfadministration.
33. The use of claim 32, wherein the self-administration is via a pre-filled syringe or auto-injector syringe.
34. The use of any one of claims 24-26, wherein the double stranded RNAi agent, or salt thereof, is to be chronically stered to the subject. 21663224_1 ters) P107927.NZ.1 PC Tritosomes 1 <<<<<<<<<<<<<<<<<<<<<<<
NZ778442A 2016-07-28 Transthyretin (TTR) iRNA compositions and methods of use thereof for treating or preventing TTR-associated diseases NZ778442B2 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US201562199563P 2015-07-31 2015-07-31
US201662287518P 2016-01-27 2016-01-27
NZ739169A NZ739169B2 (en) 2016-07-28 TRANSTHYRETIN (TTR) iRNA COMPOSITIONS AND METHODS OF USE THEREOF FOR TREATING OR PREVENTING TTR-ASSOCIATED DISEASES

Publications (2)

Publication Number Publication Date
NZ778442A NZ778442A (en) 2025-05-30
NZ778442B2 true NZ778442B2 (en) 2025-09-02

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