RNA interference mediated inhibition of hepatitis B virus (HBV) gene expression using short interfering nucleic acid (siNA)

Patent metadata

Field	Value
Publication number	US-9879262-B2
Application number	US-201615251155-A
Country	US
Kind code	B2
Filing date	Aug 30, 2016
Priority date	Aug 17, 2010
Publication date	Jan 30, 2018
Grant date	Jan 30, 2018

Abstract

The present invention relates to compounds, compositions, and methods for the study, diagnosis, and treatment of traits, diseases and conditions that respond to the modulation of HBV gene expression and/or activity, and/or modulate a HBV gene expression pathway. Specifically, the invention relates to double-stranded nucleic acid molecules including small nucleic acid molecules, such as short interfering nucleic acid (siNA), short interfering RNA (siRNA), double-stranded RNA (dsRNA), micro-RNA (miRNA), and short hairpin RNA (shRNA) molecules that are capable of mediating or that mediate RNA interference (RNAi) against HBV gene expression.

First claim

What we claim is:

1. A double-stranded short interfering nucleic acid (siNA) molecule comprising a sense strand comprising the nucleotide sequence 5′-BGCCgaUCCaUACUGCgGaAUsUB-3′ (SEQ ID NO:279) and an antisense strand comprising the nucleotide sequence 5′-UUCCgCagUaUggaUCggCUsU-3′ (SEQ ID NO:225),
wherein B is an inverted abasic moiety; bolded nucleotides comprise 2′-O-methyl modifications, lower case nucleotides comprise 2′-fluoro modifications, italicized nucleotides are deoxynucleotides, and s is a phosphorothioate linkage.

2. A composition comprising the double-stranded short interfering nucleic acid (siNA) according to claim 1 and a pharmaceutically acceptable carrier or diluent.

3. A composition comprising:
(a) the double-stranded short interfering nucleic acid (siNA) of claim 1 ;
(b) a cationic lipid;
(c) cholesterol;
(d) DSPC; and
(e) PEG-DMG.

4. A composition comprising:
(a) the double-stranded short interfering nucleic acid (siNA) of claim 1 ;
(b) (13Z,16Z)—N,N-dimethyl-3-nonyldocosa-13,16-dien-1-amine;
(c) cholesterol;
(d) DSPC; and
(e) PEG-DMG.

5. The composition according to claim 4 , wherein the (13Z,16Z)—N,N-dimethyl-3-nonyldocosa-13,16-dien-1-amine, cholesterol, DSPC, and PEG-DMG have a molar ratio of 50:30:10:2 respectively.

6. A composition comprising the composition according to claim 5 and a pharmaceutically acceptable carrier or diluent.

7. A kit comprising the double-stranded short interfering nucleic acid (siNA) according to claim 1 .

8. A method of treating a human subject suffering from a condition which is mediated by the action, or by loss of action, of Hepatitis B Virus (HBV), which comprises administering to said subject an effective amount of the double-stranded short interfering nucleic acid (siNA) molecule of claim 1 , thereby treating the human subject suffering from a condition which is mediated by the action, or by loss of action, of HBV.

9. The method according to claim 8 , wherein the condition is HBV infection.

10. The method according to claim 8 , wherein the condition is hepatocellular carcinoma.

11. The method of claim 8 , wherein the condition is a liver disease.

12. The method of claim 11 , wherein the liver disease is cirrhosis.

13. A method of treating a human subject suffering from Hepatitis B Virus (HBV) infection to reduce the progression of HBV to hepatocellular carcinoma, comprising administering to said subject an effective amount of the double-stranded short interfering nucleic acid (siNA) molecule of claim 1 , thereby treating the human subject suffering from Hepatitis B Virus (HBV) infection to reduce the progression of HBV to hepatocellular carcinoma.

14. A method of treating a human subject suffering from hepatocellular carcinoma, comprising administering to said subject an effective amount of the double-stranded short interfering nucleic acid (siNA) molecule of claim 1 and an anti-cancer agent, thereby treating the human subject suffering from hepatocellular carcinoma.

15. The method of claim 14 , wherein the chemotherapeutic agent is sorafenib.

Assignees

• Sirna Therapeutics Inc

Inventors

• Bartz Steven
• Brown Duncan
• Robinson Michael

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P31/20

  for DNA viruses · CPC title

• A61P1/16

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

• C12N2310/322

  2'-R Modification · CPC title

• C12N2310/3531

  Hydrogen · CPC title