Angiotensinogen (AGT) iRNA compositions and methods of use thereof

Patent metadata

Field	Value
Publication number	US-11015201-B2
Application number	US-202017093816-A
Country	US
Kind code	B2
Filing date	Nov 10, 2020
Priority date	May 14, 2018
Publication date	May 25, 2021
Grant date	May 25, 2021

Abstract

The present invention relates to RNAi agents, e.g., double stranded RNA (dsRNA) agents, targeting the AGT gene. The invention also relates to methods of using such RNAi agents to inhibit expression of an AGT gene and to methods of preventing and treating an AGT-associated disorder, e.g., high blood pressure.

First claim

We claim:

1. A double stranded RNA (dsRNA) agent, or a salt thereof, for inhibiting expression of angiotensinogen (AGT) in a cell, comprising a sense strand and an antisense strand forming a double stranded region,
wherein the sense strand comprises the nucleotide sequence 5′-gsuscaucCfaCfAfAfugagaguaca-3′ (SEQ ID NO:482) and the antisense strand comprises the nucleotide sequence 5′-usGfsuac(Tgn)cucauugUfgGfaugacsgsa-3′ (SEQ ID NO:666),
wherein a, g, c, and u are 2′-O-methyl (2′-OMe) A, G, C, and U, respectively; Af, Gf, Cf and Uf are 2′-fluoro A, G, C and U, respectively; s is a phosphorothioate linkage; and (Tgn) is a thymidine-glycol nucleic acid (GNA) S-Isomer.

2. The dsRNA agent, or salt thereof, of claim 1 , further comprising a ligand.

3. The dsRNA agent, or salt thereof, of claim 2 , wherein the ligand is conjugated to the 3′ end of the sense strand of the dsRNA agent, or salt thereof.

4. The dsRNA agent, or salt thereof, of claim 2 , wherein the ligand is an N-acetylgalactosamine (GalNAc) derivative.

5. The dsRNA agent, or salt thereof, of claim 2 , wherein the ligand is one or more GalNAc derivatives attached through a monovalent, bivalent, or trivalent branched linker.

6. The dsRNA agent, or salt thereof, of claim 4 , wherein the ligand is

7. The dsRNA agent, or salt thereof, of claim 6 , wherein the dsRNA agent, or salt thereof, is conjugated to the ligand as shown in the following schematic

and, wherein X is O or S.

8. The dsRNA agent, or salt thereof, of claim 7 , wherein the X is O.

9. A double stranded RNA (dsRNA) agent, or a salt thereof, for inhibiting expression of angiotensinogen (AGT) in a cell, comprising a sense strand and an antisense strand forming a double stranded region,
wherein the sense strand comprises the nucleotide sequence 5′-gsuscaucCfaCfAfAfugagaguaca-3′ (SEQ ID NO:482) and the antisense strand comprises the nucleotide sequence 5′-usGfsuac(Tgn)cucauugUfgGfaugacsgsa-3′ (SEQ ID NO:666),
wherein a, g, c, and u are 2′-O-methyl (2′-OMe) A, G, C, and U, respectively; Af, Gf, Cf and Uf are 2′-fluoro A, G, C and U, respectively; s is a phosphorothioate linkage; and (Tgn) is a thymidine-glycol nucleic acid (GNA)S-Isomer; and
wherein the 3′-end of the sense strand is conjugated to a ligand as shown in the following schematic

wherein X is O.

10. The dsRNA agent, or a salt thereof, of claim 9 , which is in a salt form.

11. A pharmaceutical composition for inhibiting expression of a gene encoding AGT comprising the dsRNA agent, or salt thereof, of claim 1 .

12. A pharmaceutical composition for inhibiting expression of a gene encoding AGT comprising the dsRNA agent, or salt thereof, of claim 9 .

13. A double stranded RNA (dsRNA) agent, or a salt thereof, for inhibiting expression of angiotensinogen (AGT) in a cell, comprising a sense strand and an antisense strand forming a double stranded region,
wherein the sense strand consists of the nucleotide sequence 5′-gsuscaucCfaCfAfAfugagaguaca-3′ (SEQ ID NO:482) and the antisense strand consists of the nucleotide sequence 5′-usGfsuac(Tgn)cucauugUfgGfaugacsgsa-3′ (SEQ ID NO:666),
wherein a, g, c, and u are 2′-O-methyl (2′-OMe) A, G, C, and U, respectively; Af, Gf, Cf and Uf are 2′-fluoro A, G, C and U, respectively; s is a phosphorothioate linkage; and (Tgn) is a thymidine-glycol nucleic acid (GNA)S-Isomer; and
wherein the 3′-end of the sense strand is conjugated to a ligand as shown in the following schematic

wherein X is O.

14. The dsRNA agent, or a salt thereof, of claim 13 , which is in a salt form.

15. A pharmaceutical composition for inhibiting expression of a gene encoding AGT comprising the dsRNA agent, or salt thereof, of claim 13 .

Assignees

• Alnylam Pharmaceuticals Inc

Inventors

• Foster Donald
• Hinkle Gregory
• Schlegel Mark K

Classifications

• C12N2310/351

  Conjugate · CPC title

• C12N2310/343

  having patterns, e.g. ==--==--==-- · CPC title

• C12N2310/322

  2'-R Modification · CPC title

• C12N2310/321

  2'-O-R Modification · CPC title

• C12N2310/32

  of the sugar · CPC title