Antisense modulation of bcl-x expression

Abstract

Compositions and methods are provided for modulating the expression of bcl-x. Antisense compounds, particularly antisense oligonucleotides, targeted to nucleic acids encoding bcl-x are preferred. Methods of using these compounds for modulation of bcl-x expression and for treatment of diseases associated with expression of bcl-x are also provided. Methods of sensitizing cells to apoptotic stimuli are also provided.

What is claimed is:  
     
         1 . An antisense compound 8 to 30 nucleobases in length targeted to a nucleic acid molecule encoding a human bcl-x, wherein said antisense compound modulates the expression of human bcl-x.  
     
     
         2 . The antisense compound of    claim 1    which is an antisense oligonucleotide.  
     
     
         3 . The antisense compound of    claim 2    wherein the antisense oligonucleotide comprises at least one modified internucleoside linkage.  
     
     
         4 . The antisense compound of    claim 3    wherein the modified internucleoside linkage of the antisense oligonucleotide is a phosphorothioate linkage, a morpholino linkage or a peptide-nucleic acid linkage.  
     
     
         5 . The antisense compound of    claim 1    wherein the antisense oligonucleotide comprises at least one modified sugar moiety.  
     
     
         6 . The antisense compound of    claim 5    wherein the modified sugar moiety of the antisense oligonucleotide is a 2′-O-methoxyethyl sugar moiety or a 2′-dimethylaminooxyethoxy sugar moiety.  
     
     
         7 . The antisense compound of    claim 5    wherein substantially all sugar moieties of the antisense oligonucleotide are modified sugar moieties.  
     
     
         8 . The antisense compound of    claim 3    wherein the antisense oligonucleotide comprises at least one modified nucleobase.  
     
     
         9 . The antisense compound of    claim 8    wherein the modified nucleobase of the antisense oligonucleotide is a 5-methylcytosine.  
     
     
         10 . The antisense compound of    claim 8    wherein each 2′-O-methoxyethyl modified cytosine nucleobase of the antisense oligonucleotide is a 5-methylcytosine.  
     
     
         11 . The antisense compound of    claim 1    which is a chimeric oligonucleotide.  
     
     
         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    further comprising a colloidal dispersion system.  
     
     
         14 . The pharmaceutical composition of    claim 12    wherein the antisense compound is an antisense oligonucleotide.  
     
     
         15 . The antisense compound of    claim 1    which is targeted to bcl-xl.  
     
     
         16 . The antisense compound of    claim 1    which is targeted to a nucleic acid molecule encoding bcl-xl and which preferentially inhibits the expression of bcl-xl.  
     
     
         17 . The antisense compound of    claim 16    which is targeted to a region of a nucleic acid molecule encoding bcl-xl which is not found in a nucleic acid molecule encoding bcl-xs.  
     
     
         18 . The antisense compound of    claim 16    which promotes apoptosis.  
     
     
         19 . The antisense compound of    claim 1    which is targeted to a region of a nucleic acid molecule encoding bcl-xs and which reduces the expression of bcl-xs.  
     
     
         20 . The antisense compound of    claim 19    which inhibits apoptosis.  
     
     
         21 . The antisense compound of    claim 1    which alters the ratio of bcl-x isoforms expressed by a cell or tissue.  
     
     
         22 . The antisense compound of    claim 21    which increases the ratio of bcl-xl to bcl-xs expressed.  
     
     
         23 . The antisense compound of    claim 21    which decreases the ratio of bcl-xl to bcl-xs expressed.  
     
     
         24 . A method of inhibiting the expression of bcl-x in human cells or tissues comprising contacting said cells or tissues with the antisense compound of    claim 1    so that expression of bcl-x is inhibited.  
     
     
         25 . A method of treating an animal having a disease or condition associated with bcl-x comprising administering to said animal a therapeutically or prophylactically effective amount of the antisense compound of    claim 1    so that expression of bcl-x is inhibited.  
     
     
         26 . A method of treating an animal having a disease or condition characterized by a reduction in apoptosis comprising administering to said human a prophylactically or therapeutically effective amount of the antisense compound of    claim 1   .  
     
     
         27 . The method of    claim 26    wherein the antisense compound is targeted to a nucleic acid molecule encoding bcl-xl and which preferentially inhibits the expression of bcl-xl.  
     
     
         28 . The pharmaceutical composition of    claim 12    further comprising a chemotherapeutic agent for the treatment of cancer.  
     
     
         29 . A method of treating cancer in an animal comprising: 
 (a) administering to the animal a pharmaceutical composition of    claim 12   ; and (b) administering to the animal a chemotherapeutic agent for the treatment of cancer.    
     
     
         30 . A method of sensitizing a cell to an apoptotic stimulus comprising treating the cell with the composition of    claim 1   .  
     
     
         31 . The method of    claim 30    wherein the apoptotic stimulus is radiation.  
     
     
         32 . The method of    claim 31    wherein the radiation is ultraviolet radiation.  
     
     
         33 . The method of    claim 30    wherein the apoptotic stimulus is a cancer chemotherapeutic drug.  
     
     
         34 . The method of    claim 33    wherein the cancer chemotherapeutic drug is VP-16, cisplatinum or taxol.  
     
     
         35 . The method of    claim 30    wherein the apoptotic stimulus is a cellular signaling molecule.  
     
     
         36 . The method of    claim 30    wherein the apoptotic stimulus is ceramide, a cytokine or staurosporine.  
     
     
         37 . The method of    claim 30    wherein said apoptotic stimulus causes mitochondrial dysfunction.  
     
     
         38 . The method of    claim 37    wherein said mitochondrial dysfunction is loss of mitochondrial membrane potential.  
     
     
         39 . The method of    claim 30   , wherein said cell is a cancer cell.  
     
     
         40 . The method of    claim 39   , wherein said cancer cells are glioblastoma or leukemia cells.  
     
     
         41 . A method of promoting apoptosis of cancer cells, comprising contacting said cells with the antisense compound of    claim 1   .  
     
     
         42 . The method of    claim 41   , further comprising the step of contacting said cells with a chemotherapeutic agent.  
     
     
         43 . The method of    claim 42   , wherein said chemotherapeutic agent is doxorubicin or dexamethasone.  
     
     
         44 . The method of    claim 42   , wherein said cancer cells are glioblastoma cells or leukemia cells.