Compositions and Methods for Inhibiting Expression of RRM2 Genes

Abstract

The invention relates to a double-stranded ribonucleic acid (dsRNA) for inhibiting the expression of a RRM2 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 the expression of a RRM2 gene using said pharmaceutical composition; and methods for inhibiting the expression of RRM2 in a cell.

We claim: 
     
         1 . A double-stranded ribonucleic acid molecule capable of inhibiting the expression of ribonucleotide reductase M2 (RRM2) gene in vitro by at least 70% comprising a sense strand and an antisense strand wherein said sense strand comprises in order nucleotides 1-19 of SEQ ID NOs.: 9, 56, or 82. 
     
     
         2 . The double-stranded ribonucleic acid molecule of  claim 1 , wherein said sense strand is less than 30 nucleotides in length. 
     
     
         3 . The double-stranded ribonucleic acid molecule of  claim 2 , wherein said sense strand is less than 25 nucleotides in length 
     
     
         4 . The double-stranded ribonucleic acid molecule of  claim 3 , wherein said antisense strand is at least partially complementary to said first strand. 
     
     
         5 . The double-stranded ribonucleic acid molecule of  claim 4 , wherein said antisense strand is less than 30 nucleotides in length. 
     
     
         6 . The double-stranded ribonucleic acid molecule of  claim 5 , wherein said antisense strand is less than 25 nucleotides in length 
     
     
         7 . The double-stranded ribonucleic acid molecule of  claim 6  wherein said antisense strand comprises in order nucleotides 1-19 of SEQ ID NOs.: 242, 289, or 315. 
     
     
         8 . The double-stranded ribonucleic acid molecule of  claim 7 , wherein said double-stranded ribonucleic acid molecule comprises a sequence pair selected from the group consisting of SEQ ID NOs.: 9/242, 56/289, or 82/315. 
     
     
         9 . The double strand ribonucleic acid molecule of  claim 8 , wherein said sense strand or said antisense strand further comprises a 3′ overhang of 1-5 nucleotides in length. 
     
     
         10 . The double strand ribonucleic acid molecule of  claim 9 , wherein said 3′ overhang comprises two deoxythymidine nucleotides. 
     
     
         11 . The double strand ribonucleic acid molecule of  claim 10 , wherein said 3′ overhang comprises two deoxythymidine nucleotides linked by a phosphorothioate group. 
     
     
         12 . The double strand ribonucleic acid molecule of  claim 9 , wherein said 3′ overhang comprises an inverted deoxythymidine. 
     
     
         13 . The double strand ribonucleic acid molecule of  claim 8 , wherein said double-stranded ribonucleic acid molecule comprises at least one modified nucleotide. 
     
     
         14 . The double-stranded ribonucleic acid molecule of  claim 13 , wherein said modified nucleotide is selected from the group consisting 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, a 2′-deoxy-2′-fluoro modified nucleotide, a 2′-deoxy-modified nucleotide, a locked nucleotide, an abasic nucleotide, inverted deoxythymidine, 2′-amino-modified nucleotide, 2′-alkyl-modified nucleotide, morpholino nucleotide, a phosphoramidate, and a non-natural base comprising nucleotide. 
     
     
         15 . The double strand ribonucleic acid molecule of  claim 14 , wherein said double-stranded ribonucleic acid molecule comprises more than one modified nucleotide. 
     
     
         16 . The double-stranded ribonucleic acid molecule of  claim 15 , wherein said double-stranded ribonucleic acid molecule comprise at least one 2′-O-methyl modified nucleotide, 2′-deoxy-2′-fluoro modified nucleotide, at least one a nucleotide comprising a 5′-phosphorothioate group, and at least one deoxythymidine. 
     
     
         17 . The double-stranded ribonucleic acid molecule of  claim 16  wherein said comprises a modified nucleic acid sequence selected from the group consisting of SEQ ID NOs: 477, 525, 526, 552, and 553 and said antisense strand comprises a modified nucleic acid sequence selected from the group consisting of: SEQ ID NOs. 839, 963, 971, 979, 885, 967, 975, 983, 891, 968, 976, and 984. 
     
     
         18 . The double-stranded ribonucleic acid molecule of  claim 17 , wherein said double-stranded ribonucleic acid molecule comprises a sequence pair selected from the group consisting of: SEQ ID NOs: 477/839, 477/963, 477/971, 477/979, 525/885, 526/967, 526/975, 526/983, 552/891, 553/968, 553/976, and 553/984. 
     
     
         19 . A cell, tissue or non-human organism comprising a double-stranded ribonucleic acid molecule comprising a sense strand and an antisense strand wherein said sense strand comprises in order nucleotides 1-19 of SEQ ID NOs.: 9, 56, or 82. 
     
     
         20 . A pharmaceutical composition comprising a double-stranded ribonucleic acid molecule wherein said double-stranded ribonucleic acid molecule comprises a sense strand and an antisense strand wherein said sense strand comprises in order nucleotides 1-19 of SEQ ID NOs.: 9, 56, or 82, and a pharmaceutically acceptable carrier.