Angiotensinogen (AGT) iRNA compositions and methods of use thereof

Patent metadata

Field	Value
Publication number	US-11419942-B2
Application number	US-202017020954-A
Country	US
Kind code	B2
Filing date	Sep 15, 2020
Priority date	May 22, 2014
Publication date	Aug 23, 2022
Grant date	Aug 23, 2022

Abstract

The present invention relates to RNAi agents, e.g., double-stranded RNAi agents, targeting the angiotensinogen (AGT) gene, and methods of using such RNAi agents to inhibit expression of AGT and methods of treating subjects having an AGT-associated disorder, e.g., hypertension.

First claim

We claim:

1. A double-stranded ribonucleic acid (RNAi) agent for inhibiting expression of angiotensinogen (AGT) in a cell,
wherein said double-stranded RNAi agent comprises a sense strand and an antisense strand forming a double-stranded region,
wherein said sense strand comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from nucleotides 635-653 of SEQ ID NO:1, and said antisense strand comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides at the corresponding position of the nucleotide sequence of SEQ ID NO:2,
wherein all of the nucleotides of said sense strand and all of the nucleotides of said antisense strand are modified nucleotides, and
wherein said sense strand is conjugated to a ligand attached at the 3′-terminus.

2. The double-stranded RNAi agent of claim 1 , wherein at least one of said modified nucleotides is selected from the group consisting of a 3′-terminal deoxy-thymine (dT) nucleotide, a 2′-O-methyl modified nucleotide, a 2′-fluoro modified nucleotide, a 2′-deoxy-modified nucleotide, a locked nucleotide, an unlocked nucleotide, a conformationally restricted nucleotide, a constrained ethyl nucleotide, an abasic nucleotide, a 2′-amino-modified nucleotide, a 2′-alkyl-modified nucleotide, a morpholino nucleotide, a phosphoramidate, a non-natural base comprising nucleotide, a nucleotide comprising a 5′-phosphorothioate group, and a terminal nucleotide linked to a cholesteryl derivative or a dodecanoic acid bisdecylamide group.

3. The double-stranded RNAi agent of claim 1 , wherein at least one strand comprises a 3′ overhang of at least 1 nucleotide; or at least one strand comprises a 3′ overhang of at least 2 nucleotides.

4. The double-stranded RNAi agent of claim 1 , wherein the double-stranded region is 15-30 nucleotide pairs in length; 17-23 nucleotide pairs in length; 17-25 nucleotide pairs in length; 23-27 nucleotide pairs in length; 19-21 nucleotide pairs in length; or 21-23 nucleotide pairs in length.

5. The double-stranded RNAi agent of claim 1 , wherein each strand is independently 15-30 nucleotides in length; or 19-30 nucleotides in length.

6. The double-stranded RNAi agent of claim 1 , wherein the ligand is one or more GalNAc derivatives attached through a bivalent or trivalent branched linker.

7. The double-stranded RNAi agent of claim 1 , wherein the ligand is

8. The double-stranded RNAi agent of claim 1 , wherein the ligand is attached to the 3′ end of the sense strand.

9. The double-stranded RNAi agent of claim 8 , wherein the RNAi agent is conjugated to the ligand as shown in the following schematic

wherein X is O or S.

10. The double-stranded RNAi agent of claim 1 , wherein said RNAi agent further comprises at least one phosphorothioate or methylphosphonate internucleotide linkage.

11. The double-stranded RNAi agent of claim 1 , wherein the sense strand is 21 nucleotides in length and the antisense strand is 23 nucleotides in length.

12. A double-stranded ribonucleic acid (RNAi) agent for inhibiting expression of angiotensinogen (AGT) in a cell, wherein the double-stranded RNAi agent comprises a sense strand and an antisense strand forming a double-stranded region,
wherein the antisense strand comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of 5′-UUACUCUCAUUGUGGAUGA-3′ (SEQ ID NO:876),
wherein all of the nucleotides of the sense strand and all of the nucleotides of the antisense strand are modified nucleotides, and
wherein the sense strand is conjugated to a ligand attached at the 3′-terminus.

13. The double-stranded RNAi agent of claim 12 , wherein the antisense strand comprises at least 17 contiguous nucleotides of 5′-UUACUCUCAUUGUGGAUGA-3′ (SEQ ID NO:876).

14. The double-stranded RNAi agent of claim 12 , wherein the antisense strand comprises at least 19 contiguous nucleotides of 5′-UUACUCUCAUUGUGGAUGA-3′ (SEQ ID NO:876).

15. The double-stranded RNAi agent of claim 12 , wherein the sense strand comprises at least 15 contiguous nucleotides of 5′-UCAUCCACAAUGAGAGUAA-3′ (SEQ ID NO: 679).

16. The double-stranded RNAi agent of claim 15 , wherein the sense strand comprises at least 17 contiguous nucleotides of 5′-UCAUCCACAAUGAGAGUAA-3′ (SEQ ID NO: 679).

17. The double-stranded RNAi agent of claim 16 , wherein the sense strand comprises at least 19 contiguous nucleotides of 5′-UCAUCCACAAUGAGAGUAA-3′ (SEQ ID NO: 679).

18. The double-stranded RNAi agent of claim 12 , wherein the sense strand comprises at least 15 contiguous nucleotides of the nucleotide sequence 5′-UCAUCCACAAUGAGAGUAA-3′ (SEQ ID NO: 679) and the antisense strand comprises at least 15 contiguous nucleotides from the nucleotide sequence of 5′-UUACUCUCAUUGUGGAUGA-3′ (SEQ ID NO:876).

19. The double-stranded RNAi agent of claim 12 , wherein at least one strand comprises a 3′ overhang of at least 1 nucleotide.

20. The double-stranded RNAi agent of claim 12 , wherein at least one strand comprises a 3′ overhang of at least 2 nucleotides.

21. The double-stranded RNAi agent of claim 12 , wherein the double-stranded region is 15-19 nucleotide pairs in length.

22. The double-stranded RNAi agent of claim 21 , wherein the double-stranded region is 17-19 nucleotide pairs in length.

23. The double-stranded RNAi agent of claim 12 , wherein each strand is independently 15-30 nucleotides in length.

24. The double-stranded RNAi agent of claim 12 , wherein each strand is independently 19-30 nucleotides in length.

25. The double-stranded RNAi agent of claim 12 , wherein the ligand is one or more GalNAc derivatives attached through a bivalent or trivalent branched linker.

26. The double-stranded RNAi agent of claim 12 , wherein the ligand is:

27. The double-stranded RNAi agent of claim 12 , wherein the double stranded RNAi agent is conjugated to the ligand as shown in the following schematic

wherein X is O or S.

28. The double-stranded RNAi agent of claim 12 , wherein the double-stranded RNAi agent further comprises at least one phosphorothioate or methylphosphonate internucleotide linkage.

29. The double-stranded RNAi agent of claim 28 , wherein the phosphorothioate or methylphosphonate internucleotide linkage is at the 3′-terminus of one strand.

30. The double-stranded RNAi agent of claim 29 , wherein said strand is the antisense strand.

31. The double-stranded RNAi agent of claim 29 , wherein said strand is the sense strand.

32. The double-stranded RNAi agent of claim 28 , wherein the phosphorothioate or methylphosphonate internucleotide linkage is at the 5′-terminus of one strand.

33. The double-stranded RNAi agent of claim 32 , wherein said strand is the antisense strand.

34. The double-stranded RNAi agent of claim 32 , wherein said strand is the sense strand.

35. The double-stranded RNAi of c

Assignees

• Alnylam Pharmaceuticals Inc

Inventors

• Foster Donald
• Bettencourt Brian
• Charisse Klaus
• Hinkle Gregory
• Kuchimanchi Satyanarayana
• Maier Martin A
• Milstein Stuart

Classifications

• C12N2310/3125

  Methylphosphonates · CPC title

• C12N2310/315

  Phosphorothioates · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• C12N2310/3521

  Methyl · CPC title