RNA interference mediated inhibition of isocitrate dehydrogenase (IDH1) gene expression

1. A double-stranded short interfering nucleic acid (siNA) molecule that inhibits the expression of mutant isocitrate dehydrogenase 1 (IDH1), comprising formula (A) having a sense strand and an antisense strand:

5′-B—N X3 —(N) X2 B-3′

3′-(N) X1 —N X4 —[N3]-[N2]-[N1]-5′   (A)

wherein, the upper strand is the sense strand and the lower strand is the antisense strand of the double-stranded nucleic acid molecule;

wherein the antisense strand comprises at least 15 contiguous nucleotides of a nucleotide sequence selected from the group consisting of SEQ ID NO: 477, SEQ ID NO: 478, SEQ ID NO: 479, SEQ ID NO: 480, SEQ ID NO: 498, and SEQ ID NO: 502; and the sense strand comprises a nucleotide sequence having complementarity to the antisense nucleotide sequence;

each N is independently either a nucleotide that is unmodified or chemically modified, or a non-nucleotide;

each B is a terminal cap;

(N) X1 is 2 and represents overhanging nucleotides which each independently comprise a 2′-O-methyl modification;

(N) X2 is 2 and represents overhanging nucleotides which each independently comprise a 2′-O-methyl modification or which each independently comprise a thymine;

X3 is an integer from 18 to 24;

X4 is an integer from 15 to 21; and,

[N1]-[N2]-[N3] are modified nucleotides or ribonucleotides.

2. A double-stranded siNA molecule according to claim 1 , comprising one or more phosphorothioate internucleotide linkages.

3. A composition comprising a double-stranded siNA molecule of claim 1 in a pharmaceutically acceptable carrier or diluent.

4. A method of treating a human subject suffering from a condition that is mediated by the action or loss of action of mutant IDH1, which comprises administering to said subject an effective amount of a double-stranded siNA molecule according to claim 1 ; or,

(b) a composition according to claim 3 .

5. The method according to claim 4 , wherein the condition is cancer.

6. The method of claim 5 , wherein the cancer is cancer of the central nervous system.

7. The method of claim 6 , wherein cancer of the central nervous system is glioma.

8. The method of claim 5 , wherein the cancer is acute myeloid leukemia (AML).

9. The method of claim 4 , further comprising administering to the subject an additional therapeutic agent.

10. The method of claim 9 , wherein the additional therapeutic agent is an anti-cancer agent.

11. The double-stranded siNA molecule according to claim 1 , wherein the sense strand comprises at least 15 nucleotides of a nucleotide sequence selected from the group consisting of SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:40, SEQ ID NO:41, SEQ ID NO:59, and SEQ ID NO:63.

12. The double-stranded siNA molecule according to claim 1 , wherein the sense and antisense strands comprise nucleotide sequences selected from the group consisting of

5′-CAUCAUAGGUUGUCAUGCU-3′

(SEQ ID NO: 38) 

and

5′-AGCAUGACAACCUAUGAUG-3′;

(SEQ ID NO: 477)

5′-AUCAUAGGUUGUCAUGCUU-3′

(SEQ ID NO: 39) 

and

5′-AAGCAUGACAACCUAUGAU-3′;

(SEQ ID NO: 478)

5′-UCAUAGGUUGUCAUGCUUA-3′

(SEQ ID NO: 40) 

and

5′-UAAGCAUGACAACCUAUGA-3′;

(SEQ ID NO: 479)

5′-CAUAGGUUGUCAUGCUUAU-3′

(SEQ ID NO: 41) 

and

5′-AUAAGCAUGACAACCUAUG-3′;

(SEQ ID NO: 480)

5′-CAUAGGUCAUCAUGCUUAU-3′

(SEQ ID NO: 59) 

and

5′-AUAAGCAUGAUGACCUAUG-3′;

(SEQ ID NO: 498) 

and

5′-GGUCAUCAUGCUUAUGGGG-3′

(SEQ ID NO: 63) 

and

5′-CCCCAUAAGCAUGAUGACC-3′.

(SEQ ID NO: 502)

13. The double-stranded siNA molecule according to claim 12 , wherein the sense and antisense strands comprise nucleotide sequences selected from the group consisting of

5′-B CAUAGGUUGUCAUGCUUAU U s U  B-3′

(SEQ ID NO: 230)

and

5′-AUAAGCAUGACAACCUAUG U s U -3′;

(SEQ ID NO: 231)

5′-B CAUCAUAGGUUGUCAUGCU U s U  B-3′

(SEQ ID NO: 198)

and

5′-AGCAUGACAACCUAUGAUG U s U -3′;

(SEQ ID NO: 199)

5′-B AUCAUAGGUUGUCAUGCUU U s U  B-3′

(SEQ ID NO: 212)

and

5′-AAGCAUGACAACCUAUGAU U s U -3′;

(SEQ ID NO: 213)

5′-B CAUAGGUCAUCAUGCUUAU TT  B-3′

(SEQ ID NO: 302)

and

5′-AUAAGCAUGAUGACCUAUG UU -3′;

(SEQ ID NO: 303)

and

5′-B GGUCAUCAUGCUUAUGGGG TT  B-3′

(SEQ ID NO: 410)

and

5′-CCCCAUAAGCAUGAUGACC UU -3′,

(SEQ ID NO: 411)

wherein A, C, G, and U are ribose A, C, G or U; A , G , C , and U are 2′-O-methyl (2′-OMe) A, G, C, or U; B is an inverted abasic cap; and T is a thymine.

14. The double-stranded siNA molecule according to claim 13 , wherein the inverted abasic cap is an inverted abasic sugar moiety.