Compounds and methods for pharmico-gene therapy of epithelial sodium channel associated disorders

Abstract

Agents and methods to alter epithelial sodium channel (ENaC) activity.

1 - 32 . (canceled) 
     
     
         33 . A method to inhibit or treat a condition associated with increased ENaC levels or increased ENaC activity, comprising: contacting a mammal at risk of or having the condition with an effective amount of an agent that inhibits or decreases transcription of one or more ENaC subunit genes and/or alters the level, amount or activity of a molecule that alters transcription of one or more ENaC subunit genes, and enhances the efficacy of gene therapy vectors. 
     
     
         34 . A method to inhibit or treat a condition associated with increased ENaC levels or increased ENaC activity, comprising: contacting a mammal at risk of or having the condition with an effective amount of an agent that inhibits or decreases transcription of one or more ENaC subunit genes and/or alters the level, amount or activity of a molecule that alters transcription of one or more ENaC subunit genes, wherein the agent is a proteasome modulating agent, and wherein the agent is not a gene or gene product encoded by the genome of the mammal, the complement of the gene, or a portion of the gene or its complement. 
     
     
         35 . A method to inhibit or treat a condition associated with increased ENaC levels or increased ENaC activity, comprising: contacting a mammal at risk of or having the condition with an effective amount of an agent that inhibits or decreases transcription of the α, β, and γ subunits of ENaC or alters the level, amount or activity of a molecule that alters transcription of the α, β, and γ subunits of ENaC. 
     
     
         36 . A method to inhibit or treat a condition associated with increased ENaC levels or increased ENaC activity, comprising: contacting a mammal at risk of or having the condition with an effective amount of an agent that inhibits or decreases transcription of one or more ENaC subunit genes and/or alters the level, amount or activity of a molecule that alters transcription of one or more ENaC subunit genes, and enhances transduction of viruses which infect mammalian cells. 
     
     
         37 . The method of any one of  claims 33  to  36  wherein the agent is epoxomicin, doxorubicin, doxil, daunorubicin, epirubicin, idarubicin, aclarubicin camptothecin, simvastatin, tannic acid or cisplatin. 
     
     
         38 . The method of any one of  claims 33  to  36  wherein the agent is a chemotherapeutic. 
     
     
         39 . The method of any one of  claims 33  to  36  wherein the agent is an antibiotic. 
     
     
         40 . The method of any one of  claims 33  to  36  wherein the agent is a food additive. 
     
     
         41 . The method of any one of  claims 33  to  36  wherein the agent is a lipid lowering agent. 
     
     
         42 . The method of any one of  claims 33  to  36  wherein the agent does not alter post-translational processing of ENaC. 
     
     
         43 . The method of any one of  claims 33  to  36  wherein the agent is not TPA. 
     
     
         44 . The method of any one of  claims 33  to  36  wherein the agent modulates transcription of one or more molecules that modulate ENaC transcription. 
     
     
         45 . The method of any one of  claims 33  to  36  wherein the agent modulates transport of molecules to or from the nucleus. 
     
     
         46 . The method of any one of  claims 33  to  36  wherein the agent modulates subcellular localization of proteasomes. 
     
     
         47 . The method of any one of  claims 33  to  36  wherein the agent decreases the level of ENaC transcription by at least 2 fold relative to a corresponding mammal not contacted with the agent. 
     
     
         48 . The method of any one of  claims 33  to  36  wherein the agent decreases the level of ENaC transcription by at least 3 fold relative to a corresponding mammal not contacted with the agent. 
     
     
         49 . The method of any one of  claims 33  to  36  wherein the agent decreases the level of ENaC transcription by at least 10 fold relative to a corresponding mammal not contacted with the agent. 
     
     
         50 . The method of any one of  claims 33  to  36  further comprising contacting the mammal with a recombinant virus. 
     
     
         51 . The method of any one of  claims 33  to  36  wherein the agent is contacted with the respiratory tract of the mammal. 
     
     
         52 . The method of any one of  claims 33  to  36  wherein the agent enhances the efficacy or transduction of adenovirus, retrovirus, adeno-associated virus or lentivirus vectors. 
     
     
         53 . The method of  claim 33 ,  35  or  36  wherein the one agent is not a gene or gene product encoded by the genome of the cells, the complement of the gene, or a portion of the gene or its complement cells are mammalian kidney cells.