Isociatrate dehydrogenase and uses therof
The present invention discloses uses for the IDH gene and/or polypeptide and/or modulators thereof in the diagnosis and treatment of apoptosis-related diseases.
1 . A method for treating a subject having an apoptosis-related disease comprising administering to said subject a therapeutically effective amount of an inhibitor of an isocitrate dehydrogenase (IDH) polypeptide, wherein the IDH polypeptide has an amino acid sequence as set forth in SEQ ID NO:2 or SEQ ID NO:4 or has a sequence which is modified therefrom while retaining the biological properties of IDH, in a dosage sufficient to inhibit expression of the IDH polypeptide so as to thereby treat the subject.
2 . A method according to claim 1 , wherein the inhibitor is administered in conjunction with a chemotherapeutic agent.
3 . (canceled)
4 . A method according to claim 1 , wherein the inhibitor is a chemical molecule selected from the group consisting of 2-(4-bromo-2,3-dioxobutylthio)-1, N6-ethenoadenosine 2′,5′-bisphosphate, NADP oxoglutatrate, o-(carboxymethyl)oxalohydroxamate, oxalylglycine, 3-bromo-2-ketoglutarate, beta-mercapto-alpha-ketoglutarate, beta-methylmercapto-alpha-ketoglutarate, beta-methylmercapto-alpha-hydroxyglutarate, adriamycin and alpha-methylisocitrate.
5 . A method according to claim 1 , wherein the inhibitor is an AS fragment comprising consecutive nucleotides having a sequence as set forth in SEQ ID NO:5.
6 . A method according to claim 1 , wherein the apoptosis-related disease is a cancer.
7 . A method for potentiating a chemotherapeutic treatment of a subject having an apoptosis-related disease comprising administering to said subject a therapeutically effective amount of an inhibitor of a human isocitrate dehydrogenase (IDH) polypeptide in conjunction with a chemotherapeutic agent so as to thereby treat the subject; wherein the IDH polypeptide has an amino acid sequence as set forth in SEQ ID NO:2 or SEQ ID NO:4 or has a sequence which is modified therefrom while retaining the biological properties of IDH.
8 . (canceled)
9 . A method according to claim 7 , wherein the inhibitor is a chemical molecule selected from the group consisting of 2-(4-bromo-2,3-dioxobutylthio)-1, N6-ethenoadenosine 2′,5′-bisphosphate, NADP oxoglutatrate, o-(carboxymethyl)oxalohydroxamate, oxalylglycine, 3-bromo-2-ketoglutarate, beta-mercapto-alpha-ketoglutarate, beta-methylmercapto-alpha-ketoglutarate, beta-methylmercapto-alpha-hydroxyglutarate, adriamycin and alpha-methylisocitrate.
10 . A method according to claim 7 , wherein the inhibitor is an AS fragment comprising consecutive nucleotides having the a sequence as set forth in SEQ ID NO:5.
11 . A method according to claim 7 , wherein the apoptosis-related disease is a cancer.
12 . An antisense oligonucleotide capable of inhibiting the expression of the IDH polypeptide, having a sequence as set forth in SEQ ID NO:5.
13 . An expression vector comprising a nucleic acid encoding the antisense oligonucleotide of claim 12 .
14 .- 24 . (canceled)
25 . A method of sensitizing a cancerous cell to apoptosis comprising the step of contacting the cell with an inhibitor of isocitrate dehydrogenase (IDH).
26 . The method according to claim 25 , wherein the inhibitor of isocitrate dehydrogenase (IDH) comprises an siRNA.
27 . The method according to claim 25 , wherein the inhibitor of isocitrate dehydrogenase (IDH) comprises an antisense oligonucleotide.
28 . The method according to claim 25 , wherein the apoptosis is Fas-induced or chemo-induced apoptosis.