Compositions and Methods for Inhibiting Expression of RRM2 Genes
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.
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.