Antisense modulation of human MDM2 expression

Abstract

Compounds, compositions and methods are provided for inhibiting the expression of human mdm2. The compositions include antisense compounds 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 antisense compound 8 to 30 nucleobases in length targeted to the 5′ untranslated region, translation termination codon region or 3′ untranslated region of a nucleic acid molecule encoding human mdm2, wherein said antisense compound modulates the expression of human mdm2.  
     
     
         2 . The antisense compound of    claim 1    wherein said antisense compound inhibits the expression of human mdm2.  
     
     
         3 . The antisense compound of    claim 1    which is an antisense oligonucleotide.  
     
     
         4 . An antisense compound up to 30 nucleobases in length comprising at least an 8-nucleobase portion of 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, SEQ ID NO: 21, SEQ ID NO: 36, SEQ ID NO: 52, SEQ ID NO: 216, SEQ ID NO: 246, SEQ ID NO: 251, SEQ ID NO: 260, or SEQ ID NO: 264 which inhibits the expression of human mdm2.  
     
     
         5 . The antisense compound of    claim 2    which is targeted to the 5′ untranslated region of the S-mdm2 transcript.  
     
     
         6 . The antisense compound of    claim 5    comprising SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5 or SEQ ID NO: 7.  
     
     
         7 . The antisense compound of    claim 2    comprising SEQ ID NO: 4.  
     
     
         8 . The antisense compound of    claim 1    which contains at least one phosphorothioate intersugar linkage.  
     
     
         9 . The antisense compound of    claim 1    which has at least one 2′-O-methoxyethyl modification.  
     
     
         10 . The antisense compound of    claim 1    which contains at least one 5-methyl cytidine.  
     
     
         11 . The antisense compound of    claim 10    in which every 2′-O-methoxyethyl modified cytidine residue is a 5-methyl cytidine.  
     
     
         12 . A pharmaceutical composition comprising the antisense compound of    claim 1    and a pharmaceutically acceptable carrier or diluent.  
     
     
         13 . The pharmaceutical composition of    claim 12    wherein said pharmaceutically acceptable carrier or diluent further comprises a lipid or liposome.  
     
     
         14 . A method of modulating the expression of human mdm2 in cells or tissues comprising contacting said cells or tissues with the antisense compound of    claim 1   .  
     
     
         15 . A method of reducing hyperproliferation of human cells comprising contacting proliferating human cells with the antisense compound of    claim 2    or a pharmaceutical composition comprising said antisense compound.  
     
     
         16 . 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 antisense compound of    claim 1   .  
     
     
         17 . The method of    claim 16    wherein the disease or condition is associated with overexpression of mdm2 and the antisense compound inhibits the expression of mdm2.  
     
     
         18 . The method of    claim 16    wherein the disease or condition is associated with amplification of the mdm2 gene and the antisense compound inhibits the expression of mdm2.  
     
     
         19 . The method of    claim 16    wherein the disease or condition is a hyperproliferative condition and the antisense compound inhibits the expression of mdm2.  
     
     
         20 . The method of    claim 19    wherein the hyperproliferative condition is cancer.  
     
     
         21 . The method of    claim 20    wherein the cancer is a blood, brain, breast, lung or a soft tissue cancer.  
     
     
         22 . The method of    claim 19    wherein the hyperproliferative condition is psoriasis, fibrosis, atherosclerosis or restenosis.  
     
     
         23 . The method of    claim 16    wherein said antisense compound is administered in combination with a chemotherapeutic agent to overcome drug resistance.  
     
     
         24 . An antisense compound up to 30 nucleobases in length targeted to the coding region or translational start site of a nucleic acid molecule encoding human mdm2, wherein said antisense compound inhibits the expression of said human mdm2 and comprises at least an 8-nucleobase portion of SEQ ID NO: 15, SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 69, SEQ ID NO: 70, SEQ ID NO: 72, SEQ ID NO: 120, SEQ ID NO: 126, SEQ ID NO: 160, SEQ ID NO: 177, SEQ ID NO: 180, or SEQ ID NO: 195.  
     
     
         25 . The antisense compound of    claim 24    which contains at least one phosphorothioate intersugar linkage.  
     
     
         26 . The antisense compound of    claim 24    which has at least one 2′-O-methoxyethyl modification.  
     
     
         27 . The antisense compound of    claim 24    which contains at least one 5-methyl cytidine.  
     
     
         28 . The antisense compound of    claim 27    in which every 2′-O-methoxyethyl modified cytidine residue is a 5-methyl cytidine.  
     
     
         29 . A pharmaceutical composition comprising the antisense compound of    claim 24    and a pharmaceutically acceptable carrier or diluent.  
     
     
         30 . The pharmaceutical composition of    claim 29    wherein said pharmaceutically acceptable carrier or diluent comprises a lipid or liposome.  
     
     
         31 . A method of modulating the expression of human mdm2 in cells or tissues comprising contacting said cells or tissues with the antisense compound of    claim 24   .  
     
     
         32 . A method of reducing hyperproliferation of human cells comprising contacting proliferating human cells with the antisense compound of    claim 24   .  
     
     
         33 . A method of reducing hyperproliferation of human cells comprising contacting proliferating human cells with the pharmaceutical composition of    claim 29   .  
     
     
         34 . 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 the antisense compound of    claim 24   .  
     
     
         35 . The method of    claim 34    wherein the disease or condition is associated with overexpression of mdm2 and the antisense compound inhibits the expression of mdm2.  
     
     
         36 . The method of    claim 34    wherein the disease or condition is associated with amplification of the mdm2 gene and the antisense compound inhibits the expression of mdm2.  
     
     
         37 . The method of    claim 34    wherein the disease or condition is a hyperproliferative condition and the antisense compound inhibits the expression of mdm2.  
     
     
         38 . The method of    claim 37    wherein the hyperproliferative condition is cancer.  
     
     
         39 . The method of    claim 38    wherein the cancer is a blood, brain, breast, lung or a soft tissue cancer.  
     
     
         40 . The method of    claim 37    wherein the hyperproliferative condition is psoriasis, fibrosis, atherosclerosis or restenosis.  
     
     
         41 . The method of    claim 34    wherein said antisense compound is administered in combination with a chemotherapeutic agent to overcome drug resistance.