RNA interference mediated inhibition of catenin (cadherin-associated protein), beta 1 (CTNNB1) gene expression using short interfering nucleic acid (SINA)

Patent metadata

Field	Value
Publication number	US-9447420-B2
Application number	US-201414339067-A
Country	US
Kind code	B2
Filing date	Jul 23, 2014
Priority date	Aug 2, 2010
Publication date	Sep 20, 2016
Grant date	Sep 20, 2016

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 CTNNB1 gene expression and/or activity, and/or modulate a beta-catenin 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 CTNNB1 gene expression.

First claim

What we claim is:

1. A double-stranded short interfering nucleic acid (siNA) molecule that inhibits the expression of cadherin-associated protein, beta 1 (CTNNB1), wherein
(a) the siNA comprises a sense strand and an antisense strand;
(b) each strand is independently 19-24 nucleotides in length; and
(c) at least one strand comprises a nucleotide sequence comprising at least 17 contiguous nucleotides of SEQ NO: 194.

2. A double-stranded short interfering nucleic acid (siNA) molecule that inhibits the expression of cadherin-associated protein, beta 1 (CTNNB1), wherein
(a) the siNA comprises a sense strand and an antisense strand;
(b) each strand is independently 19-24 nucleotides in length; and
(c) the antisense strand comprises a nucleotide sequence comprising at least 17 contiguous nucleotides 5′-ACGACUAGUUCAGUUGCUU-3′ (SEQ ID NO: 194).

3. A double-stranded short interfering nucleic acid (siNA) molecule that inhibits the expression of cadherin-associated protein, beta 1 (CTNNB1), wherein
(a) the siNA comprises a sense strand and an antisense strand;
(b) each strand is independently 19-24 nucleotides in length; and
(c) the antisense strand comprises a nucleotide sequence comprising at least 17 contiguous nucleotides of 5′-AAGCAACUGAACUAGUCGU-3′ (SEQ ID NO: 5107).

4. The double-stranded short interfering nucleic acid (siNA) molecule of claim 3 , wherein the sense strand comprises a nucleotide sequence comprising at least 17 contiguous nucleotides of 5′-ACGACUAGUUCAGUUGCUU-3′ (SEQ ID NO: 194); and wherein one of more of the nucleotides are chemically modified.

5. The double-stranded short interfering nucleic acid (siNA) molecule according to any one of claims 1 - 3 , wherein at least one nucleotide is a chemically modified nucleotide.

6. The double-stranded short interfering nucleic acid (siNA) molecule according to any one of claims 1 - 4 , further comprising at least one non-nucleotide.

7. The double-stranded short interfering nucleic acid (siNA) molecule according to any one of claims 1 - 4 , wherein at least one nucleotide comprises a universal base.

8. The double-stranded short interfering nucleic acid (siNA) molecule according to any one of claims 1 - 4 , comprising at least one phosphorothioate internucleotide linkage.

9. The double-stranded short interfering nucleic acid (siNA) molecule according to any one of claims 1 - 4 , comprising a cap on the 3′-end, 5′-end or both 3′ and 5′ ends of at least one strand.

10. The double-stranded short interfering nucleic acid (siNA) molecule according to any one of claims 1 - 4 , comprising one or more 3′-overhang nucleotides on one or both strands.

11. The double-stranded short interfering nucleic acid (siNA) molecule according to any one of claims 1 - 4 , wherein the 5′ end of the antisense strand is phosphorylated.

12. The double-stranded short interfering nucleic acid (siNA) molecule of claim 10 , wherein the 3′-overhang nucleotides on at least one strand are 2′-O-methyl nucleotides.

13. The double-stranded short interfering nucleic acid (siNA) molecule of claim 12 , wherein the 2′-O-methyl nucleotides are linked with a phosphorothioate internucleotide linkage.

14. The double-stranded short interfering nucleic acid (siNA) molecule of claim 5 , wherein the chemically modified nucleotide is a 2′-deoxy-2′-fluoro nucleotide.

15. The double-stranded short interfering nucleic acid (siNA) molecule of claim 5 , wherein the chemically modified nucleotide is a 2′-deoxy nucleotide.

16. The double-stranded short interfering nucleic acid (siNA) molecule of claim 5 , wherein the chemically modified nucleotide is a 2′-O-alkyl nucleotide.

17. The double-stranded short interfering nucleic acid (siNA) molecule according to any one of claims 1 - 4 , wherein five or more pyrimidine nucleotides in one or both strands are 2′-deoxy-2′-fluoro pyrimidine nucleotides.

18. The double-stranded short interfering nucleic acid (siNA) molecule according to any one of claims 1 - 4 , wherein five or more pyrimidine nucleotides in one or both strands are 2′-O-methyl pyrimidine nucleotides.

19. The double-stranded short interfering nucleic acid (siNA) molecule according to any one of claims 1 - 4 , wherein five or more purine nucleotides in one or both strands are 2′-deoxy-2′-fluoro purine nucleotides.

20. The double-stranded short interfering nucleic acid (siNA) molecule according to any one of claims 1 - 4 , wherein five or more purine nucleotides in one or both strands are 2′-O-methyl purine nucleotides.

21. The double-stranded short interfering nucleic acid (siNA) molecule of claim 17 , wherein five or more purine nucleotides in one or both strands are 2′-O-methyl purine nucleotides.

22. The double-stranded short interfering nucleic acid (siNA) molecule of claim 18 , wherein five or more purine nucleotides in one or both strands are 2′-deoxy-2′-fluoro nucleotides.

23. A double-stranded short interfering nucleic acid (siNA) molecule that inhibits the expression of cadherin-associated protein, beta 1 (CTNNB1), comprising SEQ ID NOS: 6372 and 6374.

24. A double-stranded short interfering nucleic acid (siNA) molecule that inhibits the expression of cadherin-associated protein, beta 1 (CTNNB1), comprising SEQ ID NOS: 6372 and 6373.

25. A composition comprising:
(a) a double-stranded short interfering nucleic acid (siNA) molecule having SEQ ID NOS:6372 and 6374;
(b) (13Z,16Z)-N,N-dimethyl-3-nonyldocosa-13,16-dien-1-amine;
(c) cholesterol;
(d) DSPC; and
(e) PEG-DMG.

26. A composition comprising:
(a) a double-stranded short interfering nucleic acid (siNA) molecule having SEQ ID NOS: 6372 and 6373;
(b) (13Z,16Z)-N,N-dimethyl-3-nonyldocosa-13,16-dien-1-amine;
(c) cholesterol;
(d) DSPC; and
(e) PEG-DMG.

27. A double-stranded short interfering nucleic acid (siNA) molecule that inhibits the expression of cadherin-associated protein, beta 1 (CTNNB 1), comprising SEQ ID NOS: 6372 and 6371.

28. A double-stranded short interfering nucleic acid (siNA) molecule that inhibits the expression of cadherin-associated protein, beta 1 (CTNNB 1), comprising SEQ ID NOS: 1912 and 1913.

29. A double-stranded short interfering nucleic acid (siNA) molecule that inhibits the expression of cadherin-associated protein, beta 1 (CTNNB 1), comprising SEQ ID NOS: 1840 and 1841.

30. A composition comprising:
(a) a double-stranded short interfering nucleic acid (siNA) molecule having SEQ ID NOS: 6372 and 6371;
(b) (13Z,16Z)-N,N-dimethyl-3-nonyldocosa-13,16-dien-1-amine;
(c) cholesterol;
(d) DSPC; and
(e) PEG-DMG.

31. A composition comprising:
(a) a double-stranded short interfering nucleic acid (siNA) molecule having SEQ ID NOS: 1912 and 1913;
(b) (13Z,16Z)-N,N-dimethyl-3-nonyldocosa-13,16-dien-1-amine;
(c) cholesterol;
(d) DSPC; and
(e) PEG-DMG.

32. A composition comprising:
(a) a double-stranded short interfering nucleic acid (siNA) molecule having SEQ ID NOS: 1840 and 1841;
(b) (13Z,16Z)-N,N-dimethyl-3-nonyldocosa-13,16-dien-1-amine;
(c) cholesterol;
(d) DSPC; and
(e) PEG-DMG.

33. The double-stranded short interfering nucleic acid (siNA) molecule according to any one of claims 23 , 24 , and 27 - 29 , comprising one or more phosphorothioate internucleotide linkages.

34. A composition comprising the double-stranded

Assignees

• Sirna Therapeutics Inc

Inventors

• Brown Duncan
• Cunningham James J
• Gindy Marian
• Pickering Victoria
• Stanton Matthew G
• Stirdivant Steven M
• Strapps Walter R

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P35/02

  specific for leukemia · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C12N2310/346

  having a combination of backbone and sugar modifications · CPC title

• A61K31/713

  Double-stranded nucleic acids or oligonucleotides · CPC title