Treating hyperinsulinemia by killing beta cells with cytotoxic gene

Abstract

This invention relates to a recombinant nucleic acid for an RIP-tk (rat insulin promoter-thymidine kinase) construct that selectively targets insulin secreting cells, such as β-cells, PDX-1 positive human pancreatic ductal carcinomas, and other cells containing certain transcription factors. The present invention is useful in the treatment of hyperinsulinemia by targeting β-cells that overproduce insulin with a cytotoxic gene.

1 - 139 . (canceled)  
     
     
         140 . A method of treating hyperinsulinemia in a subject, comprising: 
 a) directly administering to a subject a nucleic acid comprising SEQ ID NO: 1operatively coupled to a cytotoxic gene, wherein the cytotoxic gene is thereby expressed in a pancreatic beta cell,    b) administering a pro-drug to said subject, wherein the prodrug is converted to a cytotoxic compound by the action of the protein encoded by said cytotoxic gene, thereby killing the beta cell and treating hyperinsulinemia.    
     
     
         141 . The method of claim  1 , where the cytotoxic gene is the thymidine kinase gene.  
     
     
         142 . The method of claim  1 , where the cytotoxic gene is the thymidine kinase gene and the prodrug is acyclovir, ganciclovir, FIAU or 6-methoxypurine arabinoside.  
     
     
         143 . A method of killing a beta cell that over-expresses insulin in a subject, the method comprising: 
 a) administering to a subject a nucleic acid comprising SEQ ID NO: 1 operatively coupled to a cytotoxic gene, wherein the cytotoxic gene is thereby expressed in a beta cell that over-expresses insulin,    b) administering a pro-drug to said subject, wherein the prodrug is converted to a cytotoxic compound by the action of the protein encoded by said cytotoxic gene and thereby killing the beta cell that over-expresses insulin.    
     
     
         144 . The method of  claim 143 , where the cytotoxic gene is the thymidine kinase gene.  
     
     
         145 . The method of  claim 143 , where the cytotoxic gene is the thymidine kinase gene and the prodrug is acyclovir, ganciclovir, FIAU or 6-methoxypurine arabinoside.  
     
     
         146 . The method of  claim 145 , wherein the administration is systemic.  
     
     
         147 . The method of  claim 145 , wherein the administration is by direct administration at the site of the beta cell.  
     
     
         148 . A method of targeting a beta cell in a subject, the method comprising administering to a subject an expression vector comprising SEQ ID NO: 1 operatively coupled to a gene, wherein the gene is thereby expressed in a pancreatic beta cell in said subject.  
     
     
         149 . The method of  claim 148 , wherein gene is a cytotoxic gene.  
     
     
         150 . A nucleic acid comprising a sequence that has at least 95% identity to SEQ ID NO: 1 operatively coupled to a cytotoxic gene.  
     
     
         151 . The nucleic acid of  claim 150 , comprising a sequence with at least 98% identity to SEQ ID NO: 1.  
     
     
         152 . The nucleic acid of  claim 150 , comprising SEQ ID NO: 1.