Compositions and methods for inhibiting gene expression of hepatitis B virus

Patent metadata

Field	Value
Publication number	US-RE48345-E
Application number	US-201615241733-A
Country	US
Kind code	E1
Filing date	Aug 19, 2016
Priority date	Jun 30, 2011
Publication date	Dec 8, 2020
Grant date	Dec 8, 2020

Abstract

The invention relates to a double-stranded ribonucleic acid (dsRNA) for inhibiting the expression of a Hepatitis B Virus gene. The invention also relates to a pharmaceutical composition comprising the dsRNA or nucleic acid molecules or vectors encoding the same together with a pharmaceutically acceptable carrier; methods for treating diseases caused by Hepatitis B Virus infection using said pharmaceutical composition; and methods for inhibiting the expression of a Hepatitis B Virus gene in a cell.

First claim

The invention claimed is:

1. A double-stranded ribonucleic acid molecule capable of inhibiting the expression of a Hepatitis B Virus gene in vitro wherein said double-stranded ribonucleic acid molecule comprises a sense strand comprising, in order, nucleotides 1-19 of SEQ ID 2, or 6 and an antisense strand at least partially complementary to the sense strand, wherein said sense strand and said antisense strand are each less than 30 nucleotides in length.

2. The double-stranded ribonucleic acid molecule of claim 1 , wherein said antisense strand comprises in order nucleotides 1-19 of SEQ ID 158 or 163.

3. The double-stranded ribonucleic acid molecule of claim 2 , wherein said double-stranded ribonucleic acid molecule comprises sequence pairs selected from the group consisting of SEQ ID NOs: 2/158 and 6/163.

4. The double-stranded ribonucleic acid molecule of claim 1 , wherein the sense strand or the antisense strand further comprises a 3′ overhang of 1-5 nucleotides in length.

5. The double-stranded ribonucleic acid molecule of claim 4 , wherein the 3′ overhang of the antisense strand comprises uracil or nucleotides which are complementary to the pregenomic RNA and/or the mRNA encoding the protein necessary for replication or pathogenesis of Hepatitis B Virus.

6. The double-stranded ribonucleic acid molecule of claim 4 , wherein the 3′ overhang of the sense strand comprises uracil or nucleotides which that are identical to the pregenomic RNA and/or the mRNA encoding the protein necessary for replication or pathogenesis of Hepatitis B Virus.

7. The double-stranded ribonucleic acid molecule of claim 1 , wherein said double-stranded ribonucleic acid molecule comprises at least one modified nucleotide selected from the group consisting of: 2′-O-methyl modified nucleotide, nucleotide comprising a 5′-phosphorothioate group, terminal nucleotide linked to a cholesteryl derivative, terminal nucleotide linked to a dodecanoic acid bisdecylamide group, 2′-deoxy- 2′-fluoro modified nucleotide, 2-deoxy-nucleotide 2′-deoxy-nucleotide, locked nucleotide, abasic nucleotide, deoxythymidine, inverted deoxythymidine, 2′-amino-modified nucleotide, 2′-alkyl-modified nucleotide, morpholino nucleotide, phosphoramidate, and non-natural base comprising nucleotide.

8. The double-stranded ribonucleic acid molecule of claim 7 , wherein said double-stranded ribonucleic acid molecule contains a 2′-O-methyl modified nucleotide, a nucleotide comprising a 5′-phosphomthioate 5′-phosphorothioate group, and a deoxythymidine.

9. The double-stranded ribonucleic acid molecule of claim 8 , wherein said sense strand or said antisense strand further comprises an overhang of 1-2 deoxythymidines.

10. The double-stranded ribonucleic acid molecule of claim 9 , wherein said double-stranded ribonucleic acid molecule comprises the sequence pairs a sequence pair selected from the group consisting of SEQ ID NOs: 322/486 and 327/491.

11. The double-stranded ribonucleic acid molecule of claim 1 , wherein said double-stranded ribonucleic acid molecule comprises a nucleic acid sequence encoding said sense strand or said antisense strand.

12. A pharmaceutical composition comprising:
a) a first and a second double-stranded ribonucleic acid molecules each as defined in claim 1 ;
b) at least one nucleic acid sequence encoding sense strands or antisense strands comprising a first and a second double-stranded ribonucleic acid molecules each as defined in claim 1 ; or,
c) a cell, tissue or non-human organism comprising a first and a second double-stranded ribonucleic acid molecules each as defined in claim 1 .

13. The A pharmaceutical composition of claim 12 wherein comprising:
a) said a first double stranded double-stranded ribonucleic acid has comprising a sense strand comprising, in order, nucleotides 1-19 of SEQ ID NO: 2 and said a second double-stranded ribonucleic acid has comprising a sense strand comprising, in order, nucleotides 1-19 of SEQ ID NO: 4 or 6; or
b) said a first double stranded double-stranded ribonucleic acid has comprising a sense strand comprising, in order, nucleotides 1-19 of SEQ ID NO: 6 and said a second double-stranded ribonucleic acid has comprising a sense strand comprising, in order, nucleotides 1-19 of SEQ ID NO: 2 or 7.

14. The pharmaceutical composition of claim 12 , further comprising a pharmaceutically acceptable carrier, stabilizer, and/or diluent.

15. A method for inhibiting the expression of a Hepatitis B Virus gene in a cell, a tissue, or an organism, the method comprising:
a) introducing into the cell, tissue, or organism the double-stranded ribonucleic acid molecule as defined in claim 1 ; and
b) maintaining the cell, tissue, or organism produced in step a) for a time sufficient to obtain degradation of the mRNA transcript of a the Hepatitis B Virus gene, thereby inhibiting expression of a Hepatitis B Virus gene in the cell, tissue, or organism.

16. The method of claim 15 , wherein inhibiting the expression of the Hepatitis B Virus gene in an organism treats or manages a pathological condition or disease caused by infection with the Hepatitis B Virus.

17. The method of claim 16 , wherein the pathological condition and disease caused by the infection with the Hepatitis B Virus is selected from the group consisting of: chronic liver disorder, inflammation, fibrotic condition, and proliferative disorder.

18. The double-stranded ribonucleic acid molecule of claim 1, wherein the sense strand comprises, in order, nucleotides 1-19 of SEQ ID NO: 2, wherein the antisense strand is at least partially complementary to the sense strand, and wherein the sense strand and the antisense strand are each less than 30 nucleotides in length.

19. The double-stranded ribonucleic acid molecule of claim 18, wherein the double-stranded ribonucleic acid molecule contains at least one modified nucleotide.

20. The double-stranded ribonucleic acid molecule of claim 19, wherein the one or more modified nucleotides are independently selected from the group consisting of: a 2′-O-methyl modified nucleotide, a nucleotide comprising a 5′-phosphorothioate group, a terminal nucleotide linked to a cholesteryl derivative, a terminal nucleotide linked to a dodecanoic acid bisdecylamide group, a 2′-deoxy-2′-fluoro-modified nucleotide, a 2′-deoxy-nucleotide, a locked nucleotide, an abasic nucleotide, a deoxythymidine, an inverted deoxythymidine, a 2′-amino-modified nucleotide, a 2′-alkyl-modified nucleotide, a morpholino nucleotide, a phosphoroamidate, and a non-natural base comprising a nucleotide.

21. The double-stranded ribonucleic acid molecule of claim 19, wherein the double-stranded ribonucleic acid molecule comprises at least one 2′-O-methyl-modified nucleotide, at least one nucleotide comprising a 5′-phosphorothioate group, and at least one deoxythymidine.

22. The double-stranded ribonucleic acid molecule of claim 21, wherein the sense strand or the antisense strand further comprises an overhang of 1 or 2 deoxythymidine(s).

23. The double-stranded ribonucleic acid molecule of claim 18, wherein the double-stranded ribonucleic acid molecule comprises the sequence pair of SEQ ID NOs: 2/158.

24. The double-stranded ribonucleic acid molecule of claim 19, wherein the sense strand, or the antisense strand, or both the sense strand and the antisense strand, further comprises a 3′ overhang of 1-5 nucleotides in length.

25. A pharmaceutical composition comprising:
a) a double-stranded ribonu

Assignees

• Arrowhead Pharmaceuticals Inc

Inventors

• Chin Daniel J
• Deckert Jochen
• Hossbach Markus
• John Matthias

Classifications

• A61K31/713 Primary

  Double-stranded nucleic acids or oligonucleotides · CPC title

• C12N15/1131 Primary

  against viruses · CPC title

• C12N2310/335

  Modified T or U · CPC title

• C12N2310/3521

  Methyl · CPC title

• C12N2310/321

  2'-O-R Modification · CPC title