Compositions And Methods For Inhibiting Expression Of GSK-3 Genes

Abstract

The invention relates to a double-stranded ribonucleic acid (dsRNA) targeting Glycogen Synthase Kinase-3 (GSK-3), and methods of using the dsRNA to inhibit expression of GSK-3.

1 . A double-stranded ribonucleic acid (dsRNA), comprising a sense strand and an antisense strand, the sense strand comprising a first sequence and the antisense strand comprising a second sequence, the second sequence comprising a region complementary to an mRNA encoding a GSK-3, and wherein said region of complementarity is less than 30 nucleotides in length. 
     
     
         2 . (canceled) 
     
     
         3 . The dsRNA of  claim 1 , the second sequence comprising a region complementary to at least 15 nucleotides of the sense strand of huGSKA-3 (SEQ ID NO:13075). 
     
     
         4 . The dsRNA of  claim 1 , the second sequence comprising a region complementary to the sense strand of huGSKA-3 (SEQ ID NO:13075). 
     
     
         5 . The dsRNA of  claim 1 , the antisense strand comprising at least 15 nucleotides of the antisense strand of huGSKA-3 (SEQ ID NO:13083). 
     
     
         6 . The dsRNA of  claim 1 , the antisense strand comprising the antisense strand of huGSKA-3 (SEQ ID NO:13083). 
     
     
         7 . The dsRNA of  claim 1 , the antisense strand consisting of the antisense strand of huGSKA-3 (SEQ ID NO:13083). 
     
     
         8 . The dsRNA of  claim 1 , the sense strand comprising at least 15 nucleotides of the sense strand of huGSKA-3 (SEQ ID NO:13075). 
     
     
         9 . The dsRNA of  claim 1 , the sense strand comprising the sense strand of huGSKA-3 (SEQ ID NO:13075). 
     
     
         10 . The dsRNA of  claim 1 , the sense strand consisting of the sense strand of huGSKA-3 (SEQ ID NO:13075). 
     
     
         11 . The dsRNA of  claim 1 , the sense strand consisting of the sense strand of huGSKA-3 (SEQ ID NO:13075) and the antisense strand consisting of the antisense strand of huGSKA-3 (SEQ ID NO:13083). 
     
     
         12 . (canceled) 
     
     
         13 . (canceled) 
     
     
         14 . (canceled) 
     
     
         15 . (canceled) 
     
     
         16 . The dsRNA of  claim 1 , wherein said dsRNA comprises at least one modified nucleotide. 
     
     
         17 . The dsRNA of  claim 16 , wherein at least one of said modified nucleotides is chosen from the group of: a 2′-O-methyl modified nucleotide, a nucleotide comprising a 5′-phosphorothioate group, and a terminal nucleotide linked to a cholesteryl derivative or dodecanoic acid bisdecylamide group. 
     
     
         18 . The dsRNA of  claim 16 , wherein said modified nucleotide is chosen from the group of: a 2′-deoxy-2′-fluoro modified nucleotide, a 2′-deoxy-modified nucleotide, a locked nucleotide, an abasic nucleotide, 2′-amino-modified nucleotide, 2′-alkyl-modified nucleotide, morpholino nucleotide, a phosphoramidate, and a non-natural base comprising nucleotide. 
     
     
         19 . The dsRNA of  claim 16 , comprising at least one 2′-O-methyl modified nucleotide and at least one nucleotide comprising a 5′-phosphorothioate group, 
     
     
         20 . The dsRNA of  claim 1 , wherein the region of complementary is at least 15 nucleotides in length. 
     
     
         21 . The dsRNA of  claim 1 , wherein the region of complementarity is between 19 and 21 nucleotides in length. 
     
     
         22 . The dsRNA of  claim 1 , wherein the region of complementarity is 19 nucleotides in length. 
     
     
         23 . The dsRNA of  claim 1 , wherein administration of the dsRNA inhibits expression of GSK3 by more than 40%. 
     
     
         24 . The dsRNA of  claim 1 , wherein the dsRNA exhibits an 1050 of less than or equal to 10 nM in suppressing GSK3. 
     
     
         25 . The dsRNA of  claim 1 , wherein the dsRNA exhibits an 1050 of less than or equal to 1.0 nM in suppressing GSK3. 
     
     
         26 . A cell comprising the dsRNA of  claim 1 . 
     
     
         27 . A vector comprising at least one strand of the dsRNA of  claim 1 . 
     
     
         28 . A cell comprising the vector of  claim 27 . 
     
     
         29 . A pharmaceutical composition for inhibiting expression of an GSK-3 gene comprising the dsRNA of  claim 1 . 
     
     
         30 . A method of inhibiting GSK-3 expression in a cell, the method comprising:
 (a) introducing into the cell the dsRNA of  claim 1 ; and   (b) maintaining the cell produced in step (a) for a time sufficient to obtain degradation of the mRNA transcript of a GSK-3 gene, thereby inhibiting expression of a GSK-3 gene in the cell.   
     
     
         31 . A method of treating a disorder mediated by GSK-3 expression comprising administering to a human in need of such treatment a therapeutically effective amount of the dsRNA of  claim 1 . 
     
     
         32 . (canceled)