RNA interference mediated inhibition of prolyl hydroxylase domain 2 (PHD2) gene expression using short interfering nucleic acid (SINA)
The present invention relates to compounds, compositions, and methods for the study, diagnosis, and treatment of traits, diseases and conditions that respond to the modulation of PHD2 gene expression and/or activity, and/or modulate a beta-catenin gene expression pathway. Specifically, the invention relates to double-stranded nucleic acid molecules including small nucleic acid molecules, such as short interfering nucleic acid (siNA), short interfering RNA (siRNA), double-stranded RNA (dsRNA), micro-RNA (miRNA), and short hairpin RNA (shRNA) molecules that are capable of mediating or that mediate RNA interference (RNAi) against PHD2 gene expression.
1. A composition comprising a double-stranded short interfering nucleic acid (siNA) molecule that inhibits expression of prolyl hydroxylase domain 2 (PHD2), and a pharmaceutically acceptable carrier or diluent,
wherein the siNA molecule comprises a sense strand and an antisense strand,
wherein the antisense strand comprises a nucleotide sequence of at least 15 contiguous nucleotides having sequence complementarity to 5′-CAUUGAACCCAAAUUUGAU-3′ (SEQ ID NO: 33), and
wherein the pharmaceutically acceptable carrier or diluent comprises
(a) a cationic lipid;
(b) cholesterol;
(c) DSPC; and
(d) PEG-DMG.
2. The composition of claim 1 , wherein the pharmaceutically acceptable carrier or diluent comprises:
(a) (13Z,16Z)-N,N-dimethyl-3-nonyldocosa-13,16-dien-1-amine;
(b) cholesterol;
(c) DSPC; and
(d) PEG-DMG.
3. The composition of claim 2 , wherein the (13Z,16Z)-N,N-dimethyl-3-nonyldocosa-13,16-dien-1-amine, cholesterol, DSPC, and PEG-DMG have a molar ratio of 50:30:10:2 respectively.
4. The composition of claim 1 , further comprising a second double stranded short interfering nucleic acid (siNA) molecule comprising a sense strand and an antisense strand, wherein the antisense strand comprises a nucleotide sequence having sequence complementarity to the nucleotide sequence of the target site 5′-CCUGUAUCUACUACCUGAA-3′ (SEQ ID NO: 1052).
5. The composition of claim 1 , wherein the sense strand comprises the nucleotide sequence 5′-CAUUGAACCCAAAUUUGAU-3′ (SEQ ID NO: 33).
6. The composition of claim 1 , wherein the antisense strand comprises the nucleotide sequence 5′-AUCAAAUUUGGGUUCAAUG-3′ (SEQ ID NO: 912).
7. A method of treating a human subject suffering from a condition which is mediated by the action, or by loss of action, of PHD2, which comprises administering to said subject an effective amount of the composition of claim 1 .
8. The method of claim 7 , wherein the condition is anemia.
9. The method of claim 7 , further comprising administration of a chemotherapeutic agent to said subject.
10. A kit comprising the composition of claim 1 .
11. The method of claim 7 , comprising administering to said subject an effective amount of the composition of claim 4 .
12. The method of claim 11 , wherein the condition is anemia.
13. The method of claim 11 , further comprising administration of a chemotherapeutic agent.