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 for inhibiting the expression of a ribonucleotide reductase M2 (RRM2) gene, wherein the double-stranded ribonucleic acid molecule comprises a sense strand and an antisense strand, wherein the antisense strand and the sense strand are each less than about 30 nucleotides in length, wherein the antisense strand comprises the nucleotide sequence of any of SEQ ID NO: 300, 331, 351, 369, 379, 393, 405 or 424, wherein the sense strand is at least substantially complementary to the antisense strand, and wherein the sense strand and/or the antisense strand comprises at least one modified nucleotide.
2. The double-stranded ribonucleic acid molecule of claim 1 , wherein the antisense strand and the sense strand are each 19-24 nucleotides in length.
3. The double-stranded ribonucleic acid molecule of claim 2 , wherein the modified nucleotide is selected from the group consisting of: 2′-O-methyl modified nucleotide, nucleotide comprising a 5′-phosphorothioate group, 2′-deoxy-2′-fluoro modified nucleotide, 2′-deoxy-modified nucleotide, locked nucleotide, abasic nucleotide, inverted deoxythymidine, 2′-amino-modified nucleotide, 2′-alkyl-modified nucleotide, morpholino nucleotide, phosphoramidate, and non-natural base comprising nucleotide.
4. The double-stranded ribonucleic acid molecule of claim 2 , wherein the sense strand and the antisense strand each comprise at least one modified nucleotide.
5. The double-stranded ribonucleic acid molecule of claim 4 , wherein the modified nucleotide in the sense strand and the modified nucleotide in the antisense strand is independently selected from the group consisting of: 2′-O-methyl modified nucleotide, nucleotide comprising a 5′-phosphorothioate group, 2′-deoxy-2′-fluoro modified nucleotide, 2′-deoxy-modified nucleotide, locked nucleotide, abasic nucleotide, inverted deoxythymidine, 2′-amino-modified nucleotide, 2′-alkyl-modified nucleotide, morpholino nucleotide, phosphoramidate, and non-natural base comprising nucleotide.
6. The double-stranded ribonucleic acid molecule of claim 1 , wherein the sense strand comprises the nucleotide sequence of any of SEQ ID NO: 67, 98, 118, 136, 147, 161, 173, or 192.
7. The double-stranded ribonucleic acid molecule of claim 6 , wherein the sense strand and/or the antisense strand further comprises a 3′ overhang of 1-5 nucleotides in length.
8. The double-stranded ribonucleic acid molecule of claim 7 , wherein the 3′ overhang comprises nucleotides linked by one or more phosphorothioate groups.
9. The double-stranded ribonucleic acid molecule of claim 8 , wherein the 3′ overhang comprises uracil.
10. The double-stranded ribonucleic acid molecule of claim 1 , wherein the antisense strand of the double-stranded ribonucleic acid molecule comprises at least one 2′-O-methyl modified nucleotide, at least one 2′-deoxy-2′-fluoro modified nucleotide, and at least one nucleotide comprising a 5′-phosphorothioate group.
11. The double-stranded ribonucleic acid molecule of claim 1 , wherein the sense strand of the double-stranded ribonucleic acid molecule comprises at least one 2′-O-methyl modified nucleotide, at least one 2′-deoxy-2′-fluoro modified nucleotide, and at least one nucleotide comprising a 5′-phosphorothioate group.
12. The double-stranded ribonucleic acid molecule of claim 6 , wherein the sense strand and the antisense strand of the double-stranded ribonucleic acid molecule each comprises at least one 2′-O-methyl modified nucleotide, at least one 2′-deoxy-2′-fluoro modified nucleotide, and at least one nucleotide comprising a 5′-phosphorothioate group.
13. The double-stranded ribonucleic acid molecule of claim 1 , wherein the double-stranded ribonucleotic acid molecule is conjugated to a ligand.
14. The double-stranded ribonucleic acid molecule of claim 6 , wherein said double-stranded ribonucleotic acid molecule is conjugated to a ligand.
15. The double stranded ribonucleic acid molecule of claim 1 , wherein the antisense strand comprises any of SEQ ID NO: 717, 779, 837, 810, 826, 811, 752, or 743.
16. The double stranded ribonucleic acid molecule of claim 6 , wherein the sense strand comprises any of SEQ ID NO: 537, 569, 589, 607, 618, 632, 644 or 663.
17. The double stranded ribonucleic acid molecule of claim 6 , wherein the antisense strand comprises any of SEQ ID NO: 717, 779, 837, 810, 826, 811, 752, or 743, and wherein the sense strand comprises any of SEQ ID NO: 467 537, 569, 589, 607, 618, 632, 644 or 663.
18. The double-stranded ribonucleic acid molecule of claim 15 , wherein the double-stranded ribonucleotic acid molecule is conjugated to a ligand.
19. The double-stranded ribonucleic acid molecule of claim 17 , wherein the double-stranded ribonucleotic acid molecule is conjugated to a ligand.
20. A pharmaceutical composition comprising: (i) the double-stranded ribonucleic acid molecule of claim 1 , and (ii) a pharmaceutically acceptable carrier.
21. A pharmaceutical composition comprising: (i) the double-stranded ribonucleic acid molecule of claim 6 , and (ii) a pharmaceutically acceptable carrier.