Antisense oligonucleotide modulation of human MDM2 expression

Abstract

Compounds, compositions and methods are provided for inhibiting the expression of human mdm2. The compositions comprise antisense oligonucleotides targeted to nucleic acids encoding mdm2. Methods of using these oligonucleotides for inhibition of mdm2 expression and for treatment of diseases such as cancers associated with overexpression of mdm2 are provided.

What is claimed is:  
     
         1 . An oligonucleotide up to 50 nucleotides in length comprising a nucleotide sequence targeted to the 5′ untranslated region, translation termination codon region, or 3′ untranslated region of a nucleic acid molecule encoding human mdm2, wherein said oligonucleotide inhibits the expression of said human mdm2.  
     
     
         2 . The oligonucleotide of  claim 1  comprising SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 7, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19 or SEQ ID NO: 21.  
     
     
         3 . The oligonucleotide of  claim 1  which is targeted to the 5′ untranslated region of the S-mdm2 transcript.  
     
     
         4 . The oligonucleotide of  claim 3  comprising SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5 OR SEQ ID NO: 7.  
     
     
         5 . The oligonucleotide of  claim 1  comprising SEQ ID NO: 4.  
     
     
         6 . The oligonucleotide of  claim 1  which contains at least one phosphorothioate intersugar linkage.  
     
     
         7 . The oligonucleotide of  claim 1  which has at least one 2′-O-methoxyethyl modification.  
     
     
         8 . The oligonucleotide of  claim 1  which contains at least one 5-methyl cytidine.  
     
     
         9 . The oligonucleotide of  claim 8  in which every 2′-O-methoxyethyl modified cytidine residue is a 5-methyl cytidine.  
     
     
         10 . A pharmaceutical composition comprising the oligonucleotide of  claim 1  and a pharmaceutically acceptable carrier or diluent.  
     
     
         11 . The pharmaceutical composition of  claim 10  where said pharmaceutically acceptable carrier or diluent comprises a lipid or liposome.  
     
     
         12 . A method of modulating the expression of human mdm2 in cells or tissues comprising contacting said cells or tissues with the oligonucleotide of  claim 1 .  
     
     
         13 . A method of reducing hyperproliferation of human cells comprising contacting proliferating human cells with the composition of  claim 1 .  
     
     
         14 . A method of reducing hyperproliferation of human cells comprising contacting proliferating human cells with the pharmaceutical composition of  claim 10 .  
     
     
         15 . A method of treating an animal having a disease or condition associated with mdm2 comprising administering to said animal a therapeutically or prophylactically effective amount of an oligonucleotide of  claim 1 .  
     
     
         16 . The method of  claim 15  wherein the disease or condition is associated with overexpression of mdm2.  
     
     
         17 . The method of  claim 15  wherein the disease or condition is associated with amplification of the mdm2 gene.  
     
     
         18 . The method of  claim 15  wherein the disease or condition is a hyperproliferative condition.  
     
     
         19 . The method of  claim 18  wherein the hyperproliferative condition is cancer.  
     
     
         20 . The method of  claim 19  wherein the cancer is a blood, brain, breast, lung or a soft tissue cancer.  
     
     
         21 . The method of  claim 18  wherein the hyperproliferative condition is psoriasis, fibrosis, atherosclerosis or restenosis.  
     
     
         22 . The method of  claim 15  wherein said oligonucleotide is administered in combination with a chemotherapeutic agent to overcome drug resistance.  
     
     
         23 . An oligonucleotide up to 50 nucleotides targeted to the coding region of a nucleic acid molecule encoding human mdm2, wherein said oligonucleotide inhibits the expression of said human mdm2 and comprises SEQ ID NO: 15.  
     
     
         24 . The oligonucleotide of  claim 23  which contains at least one phosphorothioate intersugar linkage.  
     
     
         25 . The oligonucleotide of  claim 23  which has at least one 2′-O-methoxyethyl modification.  
     
     
         26 . The oligonucleotide of  claim 23  which contains at least one 5-methyl cytidine.  
     
     
         27 . The oligonucleotide of  claim 26  in which every 2′-O-methoxyethyl modified cytidine residue is a 5-methyl cytidine.  
     
     
         28 . A pharmaceutical composition comprising the oligonucleotide of  claim 23  and a pharmaceutically acceptable carrier or diluent.  
     
     
         29 . The pharmaceutical composition of  claim 28  where said pharmaceutically acceptable carrier or diluent comprises a lipid or liposome.  
     
     
         30 . A method of modulating the expression of human mdm2 in cells or tissues comprising contacting said cells or tissues with the oligonucleotide of  claim 23 .  
     
     
         31 . A method of reducing hyperproliferation of human cells comprising contacting proliferating human cells with the composition of  claim 23 .  
     
     
         32 . A method of reducing hyperproliferation of human cells comprising contacting proliferating human cells with the pharmaceutical composition of  claim 28 .  
     
     
         33 . A method of treating an animal having a disease or condition associated with mdm2 comprising administering to said animal a therapeutically or prophylactically effective amount of an oligonucleotide of  claim 23 .  
     
     
         34 . The method of  claim 33  wherein the disease or condition is associated with overexpression of mdm2.  
     
     
         35 . The method of  claim 33  wherein the disease or condition is associated with amplification of the mdm2 gene.  
     
     
         36 . The method of  claim 33  wherein the disease or condition is a hyperproliferative condition.  
     
     
         37 . The method of  claim 36  wherein the hyperproliferative condition is cancer.  
     
     
         38 . The method of  claim 37  wherein the cancer is a blood, brain, breast, lung or a soft tissue cancer.  
     
     
         39 . The method of  claim 36  wherein the hyperproliferative condition is psoriasis, fibrosis, atherosclerosis or restenosis.  
     
     
         40 . The method of  claim 33  wherein said oligonucleotide is administered in combination with a chemotherapeutic agent to overcome drug resistance.