MicroRNA compounds and methods for modulating miR-122

Patent metadata

Field	Value
Publication number	US-10150967-B2
Application number	US-201715403672-A
Country	US
Kind code	B2
Filing date	Jan 11, 2017
Priority date	May 1, 2013
Publication date	Dec 11, 2018
Grant date	Dec 11, 2018

Abstract

Described herein are compositions and methods for the inhibition of miR-122 activity. The compositions have certain nucleoside modifications that yield potent inhibitors of miR-122 activity. The compounds may comprise conjugates to facilitate delivery to the liver. The compositions may be administered to subjects infected with hepatitis C virus, as a treatment for hepatitis C virus and related conditions.

First claim

What is claimed:

1. A method of treating an HCV infection comprising administering to an HCV-infected human a therapeutically effective amount of a pharmaceutical composition comprising a compound of the structure:

wherein X is a phosphodiester linkage; m is 1; N in N m is a β-D-deoxyriboadenosine; Y is a phosphodiester linkage; and MO is a modified oligonucleotide having the structure A E Me C E A E Me C E Me C E A E T E TGU S C S AC S AC S TC S C S (SEQ ID NO: 4), wherein the superscript “Me” indicates 5-methylcytosine, wherein nucleosides not followed by a subscript are β-D-deoxyribonucleosides, nucleosides followed by a subscript “E” are 2′-MOE nucleosides, nucleosides followed by a subscript “S” are S-cEt nucleosides, and each internucleoside linkage is a phosphorothioate internucleoside linkage; and wherein Y is linked to the 3′ terminus of the modified oligonucleotide; and one or more pharmaceutically acceptable excipients; and
at least one additional therapeutic agent.

2. The method of claim 1 , wherein the at least one therapeutic agent is selected from a protease inhibitor, a polymerase inhibitor, a cofactor inhibitor, an RNA polymerase inhibitor, a structural protein inhibitor, a non-structural protein inhibitor, a cyclophilin inhibitor, an entry inhibitor, a TLR7 agonist, and an interferon.

3. The method of claim 1 , wherein the at least one therapeutic agent is selected from a protease inhibitor, an NS5A inhibitor, an NS3/4A inhibitor, a nucleoside NS5B inhibitor, a nucleotide NS5B inhibitor, a non-nucleoside NS5B inhibitor, a cyclophilin inhibitor and an interferon.

4. The method of claim 1 , wherein the at least one therapeutic agent is selected from interferon alfa-2a, interferon alpha-2b, interferon alfacon-1, peginterferon alpha-2b, peginterferon alpha-2a, interferon-alpha-2b extended release, interferon lambda, sofosbuvir, ledipasvir, ribavirin, telapravir, boceprevir, vaniprevir, asunaprevir, ritonavir, setrobuvir, daclastavir, simeprevir, alisporivir, mericitabine, tegobuvir, danoprevir, sovaprevir, and neceprevir.

5. The method of claim 1 , wherein the at least one therapeutic agent is sofosbuvir.

6. The method of claim 1 , wherein the at least one therapeutic agent is sofosbuvir and ledipasvir.

7. The method of claim 1 , wherein the at least one therapeutic agent is daclatasvir.

8. The method of claim 1 , wherein the at least one therapeutic agent is simeprevir.

9. The method of claim 1 , wherein the administering prevents a rebound in serum HCV RNA.

10. The method of claim 1 , wherein the administering delays a rebound in serum HCV RNA.

11. The method of claim 1 , wherein the administering reduces HCV RNA level.

12. The method of claim 1 , wherein the method achieves a sustained virological response.

13. The method of claim 5 , wherein the administering reduces HCV RNA level.

14. The method of claim 6 , wherein the administering reduces HCV RNA level.

15. The method of claim 7 , wherein the administering reduces HCV RNA level.

16. The method of claim 8 , wherein the administering reduces HCV RNA level.

17. The method of claim 5 , wherein the method achieves a sustained virological response.

18. The method of claim 6 , wherein the method achieves a sustained virological response.

19. The method of claim 7 , wherein the method achieves a sustained virological response.

20. The method of claim 8 , wherein the method achieves a sustained virological response.

Assignees

• Regulus Therapeutics Inc

Inventors

• Bhat Balkrishen
• Hogan Daniel

Classifications

• A61P1/16

  for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics · CPC title

• C12N15/1131 Primary

  against viruses · CPC title

• A61K47/548

  Phosphates or phosphonates, e.g. bone-seeking (phospholipids A61K47/544) · CPC title

• C12N2320/30

  Special therapeutic applications · CPC title

• A61K47/543

  Lipids, e.g. triglycerides; Polyamines, e.g. spermine or spermidine · CPC title