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NZ780687B2 - Compositions and methods for inhibiting gene expression of LPA - Google Patents
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NZ780687B2 - Compositions and methods for inhibiting gene expression of LPA - Google Patents

Compositions and methods for inhibiting gene expression of LPA

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Publication number
NZ780687B2
NZ780687B2 NZ780687A NZ78068716A NZ780687B2 NZ 780687 B2 NZ780687 B2 NZ 780687B2 NZ 780687 A NZ780687 A NZ 780687A NZ 78068716 A NZ78068716 A NZ 78068716A NZ 780687 B2 NZ780687 B2 NZ 780687B2
Authority
NZ
New Zealand
Prior art keywords
sequence
seq
sense strand
antisense strand
nucleotide
Prior art date
Application number
NZ780687A
Other versions
NZ780687A (en
Inventor
Aaron Almeida
Lauren J Almeida
Steven Kanner
David L Lewis
Zhen Li
Stacey Melquist
Tao Pei
David B Rozema
Vladimir S Trubetskoy
Darren H Wakefield
Original Assignee
Arrowhead Pharmaceuticals Inc
Filing date
Publication date
Application filed by Arrowhead Pharmaceuticals Inc filed Critical Arrowhead Pharmaceuticals Inc
Publication of NZ780687A publication Critical patent/NZ780687A/en
Publication of NZ780687B2 publication Critical patent/NZ780687B2/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • 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
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • 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
    • C12N15/1137—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 against enzymes
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/10—Type of nucleic acid
    • C12N2310/14—Type of nucleic acid interfering nucleic acids [NA]
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/30—Chemical structure
    • C12N2310/31—Chemical structure of the backbone
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/30—Chemical structure
    • C12N2310/31—Chemical structure of the backbone
    • C12N2310/315—Phosphorothioates
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/30—Chemical structure
    • C12N2310/32—Chemical structure of the sugar
    • C12N2310/321—2'-O-R Modification
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/30—Chemical structure
    • C12N2310/35—Nature of the modification
    • C12N2310/351—Conjugate
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/30—Chemical structure
    • C12N2310/35—Nature of the modification
    • C12N2310/351—Conjugate
    • C12N2310/3517—Marker; Tag
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Y—ENZYMES
    • C12Y304/00—Hydrolases acting on peptide bonds, i.e. peptidases (3.4)
    • C12Y304/21—Serine endopeptidases (3.4.21)

Abstract

RNA interference (RNAi) agents and RNAi agent conjugates for inhibiting the expression of the LPA (apo(a)) gene are described. Pharmaceutical compositions comprising one or more LPA RNAi agents optionally with one or more additional therapeutics are also described. Delivery of the described LPA RNAi agents to liver cells in vivo provides for inhibition of LPA gene expression and treatment of cardiovascular and cardiovascular-related diseases.

Claims (41)

Claims:
1. A pre-filled syringe comprising a pharmaceutical composition comprising an LPA RNA interference (RNAi) agent and a pharmaceutically acceptable excipient, wherein the LPA RNAi agent comprises: (i) a sense strand and an antisense strand, wherein the antisense strand comprises the sequence of SEQ ID 0, wherein the sense strand comprises a sequence that is mentary to the sequence of the antisense strand; and (ii) a targeting group comprising an asialoglycoprotein receptor ligand, wherein the targeting group is conjugated to the sense strand.
2. The pre-filled syringe of claim 1, wherein the targeting group is conjugated to the 5' end of the sense strand.
3. The pre-filled e of claim 1 or 2, wherein the sense strand and antisense strand are each 19 to 26 nucleotides in length.
4. The pre-filled syringe of claim 3, wherein the sense strand and antisense strand are each 21 nucleotides in length.
5. The pre-filled e of any one of claims 1 to 4, wherein the LPA RNAi agent comprises one or two blunt ends.
6. The pre-filled syringe of claim 5, wherein the LPA RNAi agent comprises two blunt ends.
7. The pre-filled syringe of any one of claims 1 to 6, wherein the sense strand, the antisense , or both the sense and nse strand comprise one or more modified nucleotides.
8. The pre-filled e of claim 7, wherein the one or more modified nucleotides are independently selected from a 2'-modified nucleotide, a locked nucleotide, an abasic nucleotide, an ed deoxynucleotide, a morpholino nucleotide, a 2',3'-seco nucleotide mimic, or a nucleotide containing a tural base.
9. The pre-filled syringe of claim 8, wherein the ified tide is a 2'-O-methyl nucleotide, a 2'-deoxy-2'-fluoro nucleotide, a 2'-deoxynucleotide, a 2'-methoxyethyl nucleotide, a 2'-amino nucleotide, or a 2'-alkyl nucleotide.
10. The pre-filled syringe of any one of claims 1 to 9, wherein the LPA RNAi agent comprises one or more phosphorothioate internucleoside linkages.
11. The pre-filled syringe of claim 10, wherein both the sense and antisense strand independently comprise 1, 2, 3, or 4 phosphorothioate internucleoside linkages.
12. The pre-filled syringe of any one of claims 1 to 11, wherein the asialoglycoprotein receptor ligand comprises galactose, galactosamine, N-acetyl-galactosamine, or a galactose derivative.
13. The pre-filled syringe of any one of claims 1 to 12, wherein the ing group comprises: wherein NAG is N-Acetyl-Galactosamine and X is selected from the group consisting of O and S.
14. The lled syringe of any one of claims 1 to 13, wherein the antisense strand comprises the ce of SEQ ID NO:188 and the sense strand comprises the sequence of SEQ ID NO:384.
15. The pre-filled syringe of claim 14, wherein the antisense strand comprises the sequence of modified nucleotides according to SEQ ID NO: 790 and the sense strand comprises the sequence of modified nucleotides according to SEQ ID NO: 1189.
16. The pre-filled syringe of any one of claims 1 to 13, n the antisense strand comprises the sequence of SEQ ID NO:164 and the sense strand comprises the sequence of SEQ ID NO:376.
17. The pre-filled e of claim 16, wherein the antisense strand ses the sequence of modified nucleotides according to SEQ ID NO: 787 and the sense strand comprises the sequence of modified nucleotides according to SEQ ID NO: 1191.
18. The pre-filled syringe of any one of claims 1 to 13, wherein the nse strand comprises the sequence of SEQ ID NO:164 and the sense strand comprises the sequence of SEQ ID NO:357.
19. The pre-filled syringe of claim 18, wherein the antisense strand comprises the ce of modified tides according to SEQ ID NO: 709 and the sense strand comprises the sequence of modified nucleotides according to SEQ ID NO: 1135.
20. Use of an LPA RNA interference (RNAi) agent for the manufacture of a medicament for treating coronary artery disease in a subject in need thereof, wherein the LPA RNAi agent comprises: (i) a sense strand and an antisense strand, wherein the antisense strand comprises the sequence of SEQ ID NO:1280, wherein the sense strand comprises a sequence that is complementary to the sequence of the antisense strand; and (ii) a targeting group comprising an asialoglycoprotein receptor ligand, wherein the targeting group is conjugated to the sense strand.
21. Use of an LPA RNAi agent for the manufacture of a medicament for treating eral artery disease in a t in need thereof, wherein the LPA RNAi agent comprises: (i) a sense strand and an antisense strand, n the antisense strand ses the sequence of SEQ ID NO:1280, wherein the sense strand comprises a sequence that is complementary to the sequence of the antisense strand; and (ii) a targeting group comprising an asialoglycoprotein receptor ligand, n the targeting group is conjugated to the sense strand.
22. The use of claim 20 or 21, wherein the targeting group is conjugated to the 5' end of the sense strand.
23. The use of any one of claims 20 to 22, wherein the sense strand and antisense strand are each 19 to 26 nucleotides in length.
24. The use of claim 23, wherein the sense strand and antisense strand are each 21 nucleotides in length.
25. The use of any one of claims 20 to 24, wherein the LPA RNAi agent comprises one or two blunt ends.
26. The use of claim 25, wherein the LPA RNAi agent comprises two blunt ends.
27. The use of any one of claims 20 to 26, wherein the sense strand, the antisense strand, or both the sense and antisense strand comprise one or more modified nucleotides.
28. The use of claim 27, n the one or more modified nucleotides are independently ed from a 2'-modified nucleotide, a locked tide, an abasic nucleotide, an inverted ucleotide, a morpholino nucleotide, a 2',3'-seco tide mimic, or a nucleotide containing a non-natural base.
29. The use of claim 28, wherein the 2'-modified nucleotide is a 2'-O-methyl nucleotide, a 2'-deoxy-2'-fluoro tide, a 2'-deoxynucleotide, a 2'-methoxyethyl nucleotide, a 2'-amino nucleotide, or a 2'-alkyl nucleotide.
30. The use of any one of claims 20 to 29, wherein the LPA RNAi agent comprises one or more phosphorothioate internucleoside linkages.
31. The use of claim 30, wherein both the sense and antisense strand independently comprise 1, 2, 3, or 4 phosphorothioate internucleoside linkages.
32. The use of any one of claims 20 to 31, wherein the asialoglycoprotein receptor ligand comprises ose, galactosamine, or N-acetyl-galactosamine.
33. The use of any one of claims 20 to 32, wherein the targeting group comprises: wherein NAG is N-Acetyl-Galactosamine and X is selected from the group consisting of O and S.
34. The use of any one of claims 20 to 33, wherein the antisense strand comprises the sequence of SEQ ID NO:188 and the sense strand comprises the sequence of SEQ ID NO:384.
35. The use of claim 34, wherein the nse strand ses the sequence of modified nucleotides according to SEQ ID NO: 790 and the sense strand comprises the sequence of modified nucleotides according to SEQ ID NO: 1189.
36. The use of any one of claims 20 to 33, wherein the antisense strand comprises the sequence of SEQ ID NO:164 and the sense strand comprises the sequence of SEQ ID NO:376.
37. The use of claim 36, wherein the antisense strand comprises the sequence of modified nucleotides according to SEQ ID NO: 787 and the sense strand ses the sequence of modified nucleotides according to SEQ ID NO: 1191.
38. The use of any one of claims 20 to 33, wherein the antisense strand comprises the sequence of SEQ ID NO:164 and the sense strand comprises the sequence of SEQ ID
39. The use of claim 38, wherein the antisense strand comprises the sequence of modified nucleotides ing to SEQ ID NO: 709 and the sense strand comprises the sequence of modified nucleotides according to SEQ ID NO: 1135.
40. The use of any one of claims 20 to 39, wherein the medicament is formulated for administration to the subject by subcutaneous injection.
41. The use of any one of claims 20 to 40, n the medicament is formulated for administration with an additional therapeutic ed from the group consisting of an HMG CoA reductase inhibitor, ezetimibe, a PCSK9 inhibitor, a CTEP inhibitor, an ANGPTL3- targeting therapy, an APOC3-targetng therapy, and niacin. 132-WO-PCT_112016_
NZ780687A 2016-09-30 Compositions and methods for inhibiting gene expression of LPA NZ780687B2 (en)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US201562235816P 2015-10-01 2015-10-01
US201662346304P 2016-06-06 2016-06-06
US201662383221P 2016-09-02 2016-09-02
NZ741086A NZ741086B2 (en) 2016-09-30 Compositions and methods for inhibiting gene expression of lpa

Publications (2)

Publication Number Publication Date
NZ780687A NZ780687A (en) 2025-06-27
NZ780687B2 true NZ780687B2 (en) 2025-09-30

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