RNA interference mediated inhibition of catenin (cadherin-associated protein), beta 1 (CTNNB1) gene expression using short interfering nucleic acid (siNA)
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.
1. A method of treating a human subject suffering from a condition which is mediated by the action of cadherin-associated protein, beta 1 (CTNNB1), comprising administering to said subject an effective amount of a double-stranded short interfering nucleic acid (siNA) molecule that inhibits the expression of CTNNB1, wherein
(a) the siNA comprises a sense strand and an antisense strand;
(b) each strand is independently 15 to 30 nucleotides in length; and
(c) the sense strand comprises at least 15 nucleotides of the nucleotide sequence of SEQ ID NO: 5, thereby treating the human subject suffering from a condition which is mediated by the action of CTNNB1.
2. The method of claim 1 , wherein the condition is cancer.
3. The method of claim 1 , wherein the double-stranded short interfering nucleic acid (siNA) molecule is administered in a pharmaceutically acceptable carrier or diluent.
4. The method of claim 3 , wherein the pharmaceutically acceptable carrier or diluent comprises
(a) (13Z, 16Z)—N,N-dimethyl-3-nonyldocosa-13,16-dien-1-amine;
(b) cholesterol;
(c) DSPC; and
(d) PEG-DMG.
5. The method of claim 1 , wherein the antisense strand comprises at least 15 nucleotides having sequence complementarity to 5′-CUGUUGGAUUGAUUCGAAA-3′ (SEQ ID NO:5).
6. The method of claim 1 , wherein the antisense strand comprises at least a 15 nucleotide sequence of 5′-UUUCGAAUCAAUCCAACAG-3′ (SEQ ID NO:4918).
7. The method of claim 1 , wherein the sense strand of the siNA molecule comprises the nucleotide sequence 5′-B CUgUUggaUUgaUUCgaauu B-3′ (SEQ ID NO:6370) and the antisense strand of the siNA molecule comprises the nucleotide sequence 5′-uuucGAauCaAUCcAaCaGUU-3′ (SEQ ID NO:6369),
wherein A, C, G, and U are ribose A, C, G, and U; a, c, g, and u are 2′-deoxy-2′-fluoro A, C, G, and U; A, C, G, and U are 2′-O-methyl A, C, G, and U; and B is an inverted abasic nucleotide.
8. The method of claim 1 , wherein the sense strand of the siNA molecule comprises the nucleotide sequence 5′-B CUGUUGGAUUGAUUCGAAAUsUsB-3′(SEQ ID NO:2021) and the antisense strand of the siNA molecule comprises the nucleotide sequence 5′-uuucGAauCaAUCcAaCaGUsU-3′ (SEQ ID NO:2068);
wherein A, C, G, and U are ribose A, C, G, and U; a, c, g, and u are 2′-deoxy-2′-fluoro A, C, G, and U; A, C, G, and U are 2′-O-methyl A, C, G, and U; s is a phosphorothioate linkage; and B is an inverted abasic nucleotide.
9. The method of claim 1 , wherein at least one nucleotide of the double-stranded short interfering nucleic acid (siNA) molecule is a chemically modified nucleotide.
10. The method of claim 9 , wherein the chemically modified nucleotide is a 2′-deoxy-2′-fluoro nucleotide.
11. The method of claim 9 , wherein the chemically modified nucleotide is a 2′-deoxy nucleotide.
12. The method of claim 9 , wherein the chemically modified nucleotide is a 2′-O-alkyl nucleotide.
13. The method of claim 1 , wherein the double-stranded short interfering nucleic acid (siNA) molecule comprises at least one non-nucleotide.
14. The method of claim 1 , wherein at least one nucleotide of the double-stranded short interfering nucleic acid (siNA) molecule comprises a universal base.
15. The method of claim 1 , wherein the double-stranded short interfering nucleic acid (siNA) molecule comprises at least one phosphorothioate internucleotide linkage.
16. The method of claim 1 , wherein the double-stranded short interfering nucleic acid (siNA) molecule comprises a cap on the 3′-end of at least one strand.
17. The method of claim 1 , wherein the double-stranded short interfering nucleic acid (siNA) molecule comprises a cap on the 5′-end of at least one strand.
18. The method of claim 1 , wherein the double-stranded short interfering nucleic acid (siNA) molecule comprises a cap on both 3′- and 5′-ends of at least one strand.
19. The method of claim 1 , wherein the double-stranded short interfering nucleic acid (siNA) molecule comprises one or more 3′-overhang nucleotides on one or both strands.
20. The method of claim 19 , wherein the 3′-overhang nucleotides on at least one strand of the double-stranded short interfering nucleic acid (siNA) molecule are 2′-O-methyl nucleotides.
21. The method of claim 20 , wherein the 2′-O-methyl nucleotides on at least one strand of the double-stranded short interfering nucleic acid (siNA) molecule are linked with a phosphorothioate internucleotide linkage.
22. The method of claim 1 , wherein the subject is a human.
23. The method of claim 1 , wherein the double stranded siNA is administered to the subject intravenously, subcutaneously or intramuscularly.