Inhibition of Bcl-2 protein expression by liposomal antisense oligodeoxynucleotides

Abstract

The present invention provides novel compositions and methods for use in the treatment of Bcl-2-associated diseases like cancer, specifically, in the treatment of follicular lymphoma (FL). The compositions contain antisense oligonucleotides that hybridize to Bcl-2 nucleic acids, the gene products of which are known to interact with the tumorigenic protein Bcl-2. Used alone, or in conjunction with other antisense oligonucleotides, these compositions inhibit the proliferation of FL cancer cells.

What is claimed is:  
     
         1 . A composition comprising a polynucleotide that hybridizes to a Bcl-2-encoding polynucleotide and a lipid associated with said polynucleotide.  
     
     
         2 . The composition of  claim 1 , wherein said polynucleotide is an oligonucleotide having a length of between about 8 and about 50 bases.  
     
     
         3 . The composition of  claim 1 , wherein the polynucleotide hybridizes to the translation initiation site of Bcl-2 mRNA.  
     
     
         4 . The composition of  claim 3 , wherein the polynucleotide is an oligonucleotide comprising the sequence CAGCGTGCGCCATCCTTC (SEQ ID NO:1).  
     
     
         5 . The composition of  claim 1 , comprising a liposome formed from the lipid.  
     
     
         6 . The composition of  claim 5 , wherein the polynucleotide is encapsulated in the liposome.  
     
     
         7 . The composition of  claim 1 , wherein the lipid is a phosphatidylcholine, a phosphatidylglycerol, or a phosphatidylethanolamine.  
     
     
         8 . The composition of  claim 7 , wherein the lipid is dioleoylphosphatidylcholine.  
     
     
         9 . A composition comprising an expression construct that encodes a first polynucleotide that hybridizes to a Bcl-2-encoding polynucleotide, wherein said first polynucleotide is under the control of a promoter that is active in eukaryotic cells.  
     
     
         10 . A method of inhibiting a Bcl-2-associated disease comprising obtaining a polynucleotide that hybridizes to a Bcl-2-encoding polynucleotide, mixing the polynucleotide with a lipid to form a polynucleotide/lipid association, and administering said association to a cell.  
     
     
         11 . The method of  claim 10 , wherein the cell is a cancer cell.  
     
     
         12 . The method of  claim 11 , wherein said cancer cell is a follicular lymphoma cell.  
     
     
         13 . The method of  claim 10 , wherein said polynucleotide is an oligonucleotide having a length of between about 8 and about 50 bases.  
     
     
         14 . The method of  claim 10 , comprising a liposome formed from the lipid.  
     
     
         15 . The method of  claim 14 , wherein the liposome encapsulates the polynucleotide.  
     
     
         16 . The method of  claim 10 , wherein said contacting takes place in an animal.  
     
     
         17 . The method of  claim 16 , wherein said animal is a human.  
     
     
         18 . The method of  claim 17 , wherein said composition is delivered to said human in a volume of 0.50-10.0 ml per dose.  
     
     
         19 . The method of  claim 17 , wherein said composition is delivered to said human in an amount of from about 5 to about 30 mg polynucleotide per m 2 .  
     
     
         20 . The method of  claim 19 , wherein said composition is administered three times per week for eight weeks.