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NZ741086B2 - Compositions and methods for inhibiting gene expression of lpa - Google Patents
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NZ741086B2 - Compositions and methods for inhibiting gene expression of lpa - Google Patents

Compositions and methods for inhibiting gene expression of lpa Download PDF

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Publication number
NZ741086B2
NZ741086B2 NZ741086A NZ74108616A NZ741086B2 NZ 741086 B2 NZ741086 B2 NZ 741086B2 NZ 741086 A NZ741086 A NZ 741086A NZ 74108616 A NZ74108616 A NZ 74108616A NZ 741086 B2 NZ741086 B2 NZ 741086B2
Authority
NZ
New Zealand
Prior art keywords
seq
sequence
rnai agent
rza
lpa rnai
Prior art date
Application number
NZ741086A
Other versions
NZ741086A (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
Priority to NZ780687A priority Critical patent/NZ780687B2/en
Priority claimed from PCT/US2016/054729 external-priority patent/WO2017059223A2/en
Publication of NZ741086A publication Critical patent/NZ741086A/en
Publication of NZ741086B2 publication Critical patent/NZ741086B2/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 (33)

Claims:
1. An LPA RNA interference (RNAi) agent comprising a sense strand and an antisense strand, wherein the antisense strand comprises the sequence of any one of SEQ ID NO:1280, SEQ ID NO:1282, SEQ ID NO:1246, SEQ ID NO:1242, SEQ ID NO:1244, or SEQ ID 5 NO:1254, and wherein the sense strand comprises a sequence that is complementary to the sequence of the antisense strand.
2. The LPA RNAi agent of claim 1, wherein the sense strand and antisense strand are each 19 to 26 nucleotides in length.
3. The LPA RNAi agent of claim 2, wherein the sense strand and antisense strand are each 21 nucleotides in length.
4. The LPA RNAi agent of any one of claims 1 to 3, wherein the LPA RNAi agent 15 comprises one or two overhangs.
5. The LPA RNAi agent of claim 4, wherein the LPA RNAi agent comprises an overhang at the 3' end of the antisense . 20
6. The LPA RNAi agent of claim 4, wherein the LPA RNAi agent comprises an ng at the 3' end of the antisense strand and an overhang at the 3' end of the sense strand.
7. The LPA RNAi agent of any one of claims 1 to 3, wherein the LPA RNAi agent 25 comprises one or two blunt ends.
8. The LPA RNAi agent of claim 7, wherein the LPA RNAi agent comprises two blunt ends. 30
9. The LPA RNAi agent of any one of claims 1 to 8, wherein the sense strand, the antisense , or both the sense and antisense strand comprise one or more modified nucleotides.
10. The LPA RNAi agent of claim 9, wherein the one or more modified nucleotides are None set by rza MigrationNone set by rza Unmarked set by rza None set by rza MigrationNone set by rza Unmarked set by rza independently selected from a 2'-modified nucleotide, a locked nucleotide, an abasic nucleotide, an inverted deoxynucleotide, a morpholino nucleotide, a 2',3'-seco nucleotide mimic, or a nucleotide containing a non-natural base. 5
11. The LPA RNAi agent of claim 10, wherein the 2'-modified nucleotide 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.
12. The LPA RNAi agent of any one of claims 1 to 11, wherein the LPA RNAi agent 10 comprises one or more phosphorothioate internucleoside linkages.
13. The LPA RNAi agent of claim 12, n both the sense and nse strand independently comprise 1, 2, 3, or 4 phosphorothioate internucleoside linkages. 15
14. The LPA RNAi agent of any one of claims 1 to 13, wherein the LPA RNAi agent r comprises a targeting group.
15. The LPA RNAi agent of claim 14, wherein the targeting group comprises an asialoglycoprotein receptor ligand.
16. The LPA RNAi agent of claim 15, wherein the asialoglycoprotein receptor ligand comprises galactose, osamine, yl-galactosamine, or a galactose derivative.
17. The LPA RNAi agent of claim 14, wherein the ing group is (Chol-TEG), (TEG- 25 Chol), (C11-PEG3-NAG3), (C6-PEG4-NAG3), (NAG3), (NAG4), (NAG3-AA2), (NAG3- Palm), ), ), (NAG24), (NAG25), (NAG25)s, (NAG26), (NAG27), (NAG28), (NAG29), (NAG30) (NAG30)s, (NAG31), (NAG31s), (NAG32), ), (NAG34), (NAG35), (NAG36), or (NAG37). 30
18. The LPA RNAi agent of claim 17, wherein the targeting group comprises: None set by rza MigrationNone set by rza Unmarked set by rza None set by rza ionNone set by rza Unmarked set by rza n NAG is N-Acetyl-Galactosamine and X is selected from the group consisting of O and S. 5
19. The LPA RNAi agent of any one of claims 14 to 18, wherein the targeting group is conjugated to the 3' end of the sense strand.
20. The LPA RNAi agent of any one of claims 14 to 18, wherein the targeting group is ated to the 5' end of the sense strand.
21. The LPA RNAi agent of any one of claims 1 to 20, wherein: a) the antisense strand comprises the sequence of SEQ ID NO:1280 and the sense strand comprises the sequence of SEQ ID NO:1284; b) the antisense strand comprises the sequence of SEQ ID 6 and the sense 15 strand ses the sequence of SEQ ID NO:1247; c) the antisense strand comprises the sequence of SEQ ID NO:1242 and the sense strand comprises the sequence of SEQ ID NO:1243; d) the antisense strand comprises the sequence of SEQ ID NO:1244 and the sense strand comprises the sequence of SEQ ID NO:1245; 20 e) the antisense strand ses the sequence of SEQ ID NO:1254 and the sense strand comprises the sequence of SEQ ID NO:1255; f) the antisense strand comprises the sequence of SEQ ID NO:1280 and the sense strand comprises the sequence of SEQ ID NO:1260; or g) the antisense strand comprises the sequence of SEQ ID NO:1282 and the sense None set by rza MigrationNone set by rza Unmarked set by rza None set by rza ionNone set by rza ed set by rza strand comprises the sequence of SEQ ID NO:1259.
22. The LPA RNAi agent of any one of claims 1 to 21, wherein: a) the antisense strand comprises the ce of SEQ ID NO:188 and the sense 5 strand comprises the sequence of SEQ ID NO:384; b) the antisense strand comprises the sequence of SEQ ID NO:156 and the sense strand ses the sequence of SEQ ID ; c) the antisense strand comprises the sequence of SEQ ID NO:164 and the sense strand comprises the sequence of SEQ ID NO:357; 10 d) the antisense strand comprises the sequence of SEQ ID NO:164 and the sense strand comprises the sequence of SEQ ID NO:376; or e) the antisense strand comprises the sequence of SEQ ID NO:164 and the sense strand comprises the sequence of SEQ ID NO:384. 15 23. The LPA RNAi agent of claim 22, wherein the antisense strand comprises the sequence of SEQ ID NO:188 and the sense strand comprises the sequence of SEQ ID
23. NO:384.
24. The LPA RNAi agent of any one of claims 1 to 23, wherein: 20 a) the antisense strand comprises the sequence of modified nucleotides according to SEQ ID NO: 790 and the sense strand ses the sequence of modified nucleotides according to SEQ ID NO: 1189; b) the nse strand comprises the sequence of modified nucleotides according to SEQ ID NO: 637 and the sense strand comprises the ce of modified nucleotides 25 according to SEQ ID NO: 1132; c) the antisense strand comprises the sequence of modified nucleotides according to SEQ ID NO: 709 and the sense strand comprises the sequence of ed nucleotides according to SEQ ID NO: 1135; d) the antisense strand comprises the sequence of ed nucleotides according to 30 SEQ ID NO: 787 and the sense strand comprises the sequence of modified nucleotides according to SEQ ID NO: 1191; or e) the antisense strand comprises the sequence of modified nucleotides according to SEQ ID NO: 788 and the sense strand comprises the sequence of modified nucleotides according to SEQ ID NO: 1189. None set by rza MigrationNone set by rza Unmarked set by rza None set by rza MigrationNone set by rza Unmarked set by rza
25. The LPA RNAi agent of claim 24, 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.
26. A pharmaceutical composition comprising the LPA RNAi agent of any one of claims 1 to 25 and a pharmaceutically acceptable excipient.
27. Use of the LPA RNAi agent of any one of claims 1 to 25 in the cture of a 10 medicament for inhibiting LPA gene expression in a subject in need thereof.
28. The use of claim 27, n the subject has or is at risk of having cardiovascular disease. 15
29. Use of the LPA RNAi agent of any one of claims 1 to 25 in the manufacture of a medicament for treating cardiovascular disease in a subject in need thereof.
30. Use of the LPA RNAi agent of any one of claims 1 to 25 in the manufacture of a medicament for reducing Lp(a) serum levels in a subject in need thereof.
31. The LPA RNAi agent according to any one of claims 1 to 25, substantially as herein described with reference to any one or more of the examples but ing ative 25
32. The pharmaceutical ition according to claim 26, substantially as herein described with reference to any one or more of the examples but excluding comparative examples.
33. The use according to any one of claims 27 to 30, substantially as herein described 30 with reference to any one or more of the examples but excluding comparative examples. None set by rza MigrationNone set by rza Unmarked set by rza None set by rza MigrationNone set by rza Unmarked set by rza 132-WO-PCT_112016_
NZ741086A 2016-09-30 Compositions and methods for inhibiting gene expression of lpa NZ741086B2 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
NZ780687A NZ780687B2 (en) 2016-09-30 Compositions and methods for inhibiting gene expression of LPA

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
PCT/US2016/054729 WO2017059223A2 (en) 2015-10-01 2016-09-30 Compositions and methods for inhibiting gene expression of lpa

Publications (2)

Publication Number Publication Date
NZ741086A NZ741086A (en) 2023-11-24
NZ741086B2 true NZ741086B2 (en) 2024-02-27

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