Therapeutic use of cis-element decoys in vivo

Abstract

The invention provides for the use of oligodeoxynucleotide decoys for the prophylactic or therapeutic treatment of diseases associated with the binding of endogenous transcription factors to genes involved in cell growth, differentiation and signalling or to viral genes. By inhibiting endogenous trans-activating factors from binding transcription regulatory regions, the decoys modulate gene expression and thereby regulating pathological processes including inflammation, intimal hyperplasia, angiogenesis, neoplasia, immune responses and viral infection. The decoys are administered in amounts and under conditions whereby binding of the endogenous transcription factor to the endogenous gene is effectively competitively inhibited without significant host toxicity. The subject compositions comprise the decoy molecules in a context which provides for pharmacokinetics sufficient for effective therapeutic use.

What is claimed is:  
     
         1 . A method of modulating gene transcription in vivo within mammalian cells, said method comprising: 
 contacting a mammal with a composition comprising dsDNA having a sequence specific for binding to a transcription factor which modulates the transcription of at least one gene,    whereby said dsDNA is introduced into the nuclei of said cells in an amount sufficient to competitively inhibit the binding of said transcription factor to said gene,    whereby the transcription of said gene is modulated.    
     
     
         2 . A method according to  claim 1 , wherein said dsDNA is capable of episomal replication in said cell.  
     
     
         3 . A method according to  claim 1 , wherein said dsDNA consists essentially of oligonucleotides less than 100 bp in length.  
     
     
         4 . A method according to  claim 1 , wherein said composition further comprises liposomes and said dsDNA is contained within the lumen of said liposomes.  
     
     
         5 . A method according to  claim 4 , wherein said liposomes comprise lipid and a viral coat protein.  
     
     
         6 . A method according to  claim 1 , wherein said transcription factor is E2F, AP-1 or NFκB.  
     
     
         7 . A method according to  claim 1 , wherein said cells are vascular smooth muscle cells, tumor cells or endothelial cells..  
     
     
         8 . A method for treating a mammalian host to prevent restenosis, said method comprising: 
 introducing dsDNA into vascular smooth muscle cells at the site of a vascular lesion, said cells capable of resulting in restenosis as a result of neointima formation, in an amount to inhibit said neointima formation,    whereby said dsDNA is characterized by having a sequence specific for binding to a transcription factor which modulates the transcription of at least one gene, where the transcription product of said gene is necessary for proliferation of said cells.    
     
     
         9 . A composition comprising a viral coat protein-liposome containing dsDNA in the lumen of said liposome in a physiologically acceptable medium, wherein said dsDNA is characterized by having a sequence specific for binding to a transcription factor, wherein said transcription product of said gene is necessary for cell proliferation.  
     
     
         10 . A composition according to  claim 12 , wherein said viral coat is from the hemagglutinating virus Japan.  
     
     
         11 . A composition according to  claim 12 , wherein said transcription factor is E2F, AP-1 or NFκB.  
     
     
         12 . A composition according to  claim 12 , wherein said dsDNA is at a concentration in the range of about 0.1 to 20 μM.