Compositions And Methods For Inhibiting Expression Of IKK-B Gene

Abstract

The invention relates to a double-stranded ribonucleic acid (dsRNA) for inhibiting the expression of the IKK-B gene, comprising an antisense strand having a nucleotide sequence which is less that 30 nucleotides in length, generally 19-25 nucleotides in length, and which is substantially complementary to at least a part of the IKK-B gene. The invention also relates to a pharmaceutical composition comprising the dsRNA together with a pharmaceutically acceptable carrier; methods for treating diseases caused by the expression or activation of the IKK-B gene using the pharmaceutical composition; and methods for inhibiting the expression of the IKK-B gene in a cell.

1 . A double-stranded ribonucleic acid (dsRNA), comprising an antisense strand and a sense strand substantially complementary to said antisense strand, wherein the dsRNA has a duplex structure between 15 and 30 base pairs in length, and wherein the dsRNA mediates cleavage of IKK-B mRNA. 
     
     
         2 . The dsRNA of  claim 1 , wherein the dsRNA further comprises a non-nucleotide moiety. 
     
     
         3 . The dsRNA of  claim 1 , wherein the dsRNA is stabilized against nucleolytic degradation. 
     
     
         4 . The dsRNA of  claim 1 , wherein the sense strand and/or the antisense strand further comprises at least one 3′-overhang wherein the 3′-overhang comprises from 1 to 6 nucleotides. 
     
     
         5 . The dsRNA of  claim 1 , further comprising a phosphorothioate at the first internucleotide linkage at the 5′ end of the sense strand and/or the antisense strand. 
     
     
         6 . The dsRNA of  claim 1 , further comprising a phosphorothioate at the first internucleotide linkage at the 3′ end of the sense strand and/or the antisense strand. 
     
     
         7 . The dsRNA of  claim 1 , further comprising a 2′-modified nucleotide in the sense strand and/or the antisense strand. 
     
     
         8 . The dsRNA of  claim 7 , wherein the 2′-modified nucleotide comprises a modification selected from the group consisting of: 2′-deoxy, 2′-deoxy-2′-fluoro, 2′-O-methyl, 2′-O-methoxyethyl (2′-O-MOE), 2′-O-aminopropyl (2′-O-AP), 2′-O-dimethylaminoethyl (2′-O-DMAOE), 2′-O-dimethylaminopropyl (2′-O-DMAP), 2′-O-dimethylaminoethyloxyethyl (2′-O-DMAEOE), and 2′-O-N-methylacetamido (2′-O-NMA). 
     
     
         9 . The dsRNA of  claim 1 , wherein the sense strand comprises 15 or more contiguous nucleotides of the nucleotide sequence of SEQ ID NO:13. 
     
     
         10 . The dsRNA of  claim 1 , wherein the dsRNA is AL-DP-4619. 
     
     
         11 . The dsRNA of  claim 1 , wherein the antisense strand comprises 15 or more contiguous nucleotides of the nucleotide sequence of SEQ ID NO:14. 
     
     
         12 . The dsRNA of  claim 1 , wherein the sense strand comprises SEQ ID NO:25. 
     
     
         13 . The dsRNA of  claim 1 , wherein the antisense strand comprises SEQ ID NO:26. 
     
     
         14 . The dsRNA of  claim 1 , wherein the dsRNA is AL-DP-4440. 
     
     
         15 . A vector encoding at least one of the antisense strand and the sense strand of the dsRNA of  claim 1 . 
     
     
         16 . A cell comprising the dsRNA of  claim 1 . 
     
     
         17 . A method of making the dsRNA of  claim 1 , the method comprising synthesis of the dsRNA sense strand and the dsRNA antisense strand; and annealing the sense strand and the antisense strand. 
     
     
         18 . A pharmaceutical composition, comprising the dsRNA of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         19 . A method of treating a subject having a disease or disorder associated with IKK-B signaling, comprising administering to the subject in need of such treatment a therapeutically effective amount of the dsRNA of  claim 1 . 
     
     
         20 . A method of reducing the levels of IKK-B mRNA in a cell of a subject, or of IKK-B protein in a cell of a subject, comprising the step of administering the dsRNA of  claim 1  to the subject.