Patatin-like phospholipase domain containing 3 (PNPLA3) iRNA compositions and methods of use thereof

Patent metadata

Field	Value
Publication number	US-12480125-B2
Application number	US-202117241227-A
Country	US
Kind code	B2
Filing date	Apr 27, 2021
Priority date	Dec 16, 2019
Publication date	Nov 25, 2025
Grant date	Nov 25, 2025

Abstract

The present invention relates to RNAi agents, e.g., double stranded RNA (dsRNA) agents, targeting the Patatin-Like Phospholipase Domain Containing 3 (PNPLA3) gene. The invention also relates to methods of using such RNAi agents to inhibit expression of a PNPLA3 gene and to methods of preventing and treating an PNPLA3-associated disorder, e.g., Nonalcoholic Fatty Liver Disease (NAFLD).

First claim

We claim:

1 . A method of treating a subject having a disorder that would benefit from reduction in Patatin-Like Phospholipase Domain Containing 3 (PNPLA3) expression, comprising administering to the subject a therapeutically effective amount of a double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of PNPLA3, or a salt thereof,
wherein the dsRNA agent, or a salt thereof, comprises a sense strand and an antisense strand forming a double stranded region, wherein the sense strand consists of the nucleotide sequence 5′-csasuuagGfaUfAfAfugucuuaugu-3′ of SEQ ID NO:2648 and wherein the antisense strand consists of the nucleotide sequence 5′-asCfsauaAfgAfCfauuaUfcCfuaaugsgsg-3′ of SEQ ID NO: 2732, 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; and s is a phosphorothioate linkage; and wherein the 3′-end of the sense strand is conjugated to a ligand as shown in the following schematic:

wherein X is O, thereby treating the subject having the disorder that would benefit from reduction in PNPLA3 expression.

2 . The method of claim 1 , wherein the dsRNA agent, or a salt thereof, is present in a pharmaceutical composition.

3 . The method of claim 1 , wherein the dsRNA agent is in salt form.

4 . The method of claim 3 , wherein the dsRNA agent is in sodium salt form.

5 . The method of claim 1 , wherein the disorder is a PNPLA3-associated disorder.

6 . The method of claim 5 , wherein the PNPLA3-associated disorder is selected from the group consisting of fatty liver (steatosis), nonalcoholic steatohepatitis (NASH), cirrhosis of the liver, accumulation of fat in the liver, inflammation of the liver, hepatocellular necrosis, liver fibrosis, obesity, and nonalcoholic fatty liver disease (NAFLD).

7 . The method of claim 6 , wherein the PNPLA3-associated disorder is nonalcoholic steatohepatitis (NASH).

8 . The method of claim 1 , wherein the subject is human.

9 . The method of claim 1 , wherein the dsRNA agent, or a salt thereof, is administered to the subject subcutaneously.

10 . The method of claim 1 , further comprising administering to the subject an additional therapeutic agent for treatment of a PNPLA3-associated disorder.

11 . A method of treating a subject having a disorder that would benefit from reduction in Patatin-Like Phospholipase Domain Containing 3 (PNPLA3) expression, comprising administering to the subject a therapeutically effective amount of a double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of PNPLA3,
wherein the dsRNA agent comprises a sense strand and an antisense strand forming a double stranded region, wherein the sense strand comprises of the nucleotide sequence 5′-csasuuagGfaUfAfAfugucuuaugu-3′ of SEQ ID NO:2648 and wherein the antisense strand consists of the nucleotide sequence of 5′-asCfsauaAfgAfCfauuaUfcCfuaaugsgsg-3′ of SEQ ID NO: 2732, 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; and s is a phosphorothioate linkage; and wherein the 3′-end of the sense strand is conjugated to a ligand as shown in the following schematic:

wherein X is O, thereby treating the subject having the disorder that would benefit from reduction in PNPLA3 expression.

12 . The method of claim 11 , wherein the dsRNA agent, or a salt thereof, is present in a pharmaceutical composition.

13 . The method of claim 11 , wherein the dsRNA agent is in salt form.

14 . The method of claim 13 , wherein the dsRNA agent is in sodium salt form.

15 . The method of claim 11 , wherein the disorder is a PNPLA3-associated disorder.

16 . The method of claim 11 , wherein the PNPLA3-associated disorder is selected from the group consisting of fatty liver (steatosis), nonalcoholic steatohepatitis (NASH), cirrhosis of the liver, accumulation of fat in the liver, inflammation of the liver, hepatocellular necrosis, liver fibrosis, obesity, and nonalcoholic fatty liver disease (NAFLD).

17 . The method of claim 16 , wherein the PNPLA3-associated disorder is nonalcoholic steatohepatitis (NASH).

18 . The method of claim 11 , wherein the subject is human.

19 . The method of claim 11 , wherein the dsRNA agent, or a salt thereof, is administered to the subject subcutaneously.

20 . The method of claim 11 , further comprising administering to the subject an additional therapeutic agent for treatment of a PNPLA3-associated disorder.

Assignees

• Alnylam Pharmaceuticals Inc

Inventors

• Tremblay Frederic
• Mcininch James D
• Castoreno Adam
• Schlegel Mark K
• Kaittanis Charalambos

Classifications

• C12N2310/322

  2'-R Modification · CPC title

• C12N2310/351

  Conjugate · CPC title

• C12N2310/346

  having a combination of backbone and sugar modifications · CPC title

• C12N2310/3125

  Methylphosphonates · CPC title

• C12N2310/315

  Phosphorothioates · CPC title