Agents that modulate DNA-PK activity and methods of use thereof

Abstract

The present invention provides methods for modulating cell death in a eukaryotic cell, and methods for reducing DNA damage in a eukaryotic cell. The methods generally comprise modulating a biological activity of DNA-PK in a cell. The invention further provides methods of treating a condition related to cell death in an individual. The invention further provides methods of identifying agents which modulate a biological activity of DNA-PK, as well as agents identified by the methods. Methods of modulating an immune response using an identified agent are also provided.

What is claimed is:  
     
         1 . A method of modulating cell death in a eukaryotic cell, comprising contacting the cell with an agent that modulates a biological activity of DNA-PK.  
     
     
         2 . The method of  claim 1 , wherein the biological activity of DNA-PK is a kinase activity of DNA-PKcs.  
     
     
         3 . The method according to  claim 2 , wherein DNA-PKcs kinase activity is increased in the cell, thereby decreasing cell death.  
     
     
         4 . The method according to  claim 1 , wherein the agent comprises an immunomodulatory nucleic acid molecule.  
     
     
         5 . The method according to  claim 2 , wherein DNA-PKcs kinase activity is decreased in the cell, thereby increasing cell death.  
     
     
         6 . A method of reducing cell damage mediated by a hypoxic condition, comprising contacting the cell with an agent that modulates a biological activity of DNA-PK.  
     
     
         7 . The method of  claim 6 , wherein said agent is an immunomodulatory nucleic acid molecule.  
     
     
         8 . A method for identifying an agent that modulates a biological activity of DNA-PK, comprising: 
 a) adding an agent to be tested to a sample, the sample comprising DNA-PK and an immunomodulatory nucleic acid molecule, under conditions which favor binding of the immunomodulatory nucleic acid molecule to DNA-PK, thereby forming a test sample; and    b) detecting a biological activity of DNA-PK protein in the test sample, as compared to a control sample lacking the agent, wherein an increase or a decrease in the biological activity of DNA-PK indicates that the agent modulates a biological activity of DNA-PK.    
     
     
         9 . The method of  claim 8 , wherein the biological activity of DNA-PK is binding to an immunomodulatory nucleic acid molecule.  
     
     
         10 . The method according to  claim 9 , wherein the method is a cell-free method, and the immunomodulatory nucleic acid molecule is detectably labeled.  
     
     
         11 . The method of  claim 8 , wherein the biological activity of DNA-PK is activation of DNA-PKcs kinase activity.  
     
     
         12 . The method of  claim 8 , wherein the method is a cell-based method and modulation of DNA-PK activity is detected by measuring an amount of IL-6 or IL-12 produced by the cell.  
     
     
         13 . A composition comprising: 
 a) an agent identified by the method of  claim 8;  and    b) a pharmaceutically acceptable excipient.    
     
     
         14 . A method for reducing DNA damage in a eukaryotic cell, comprising contacting the cell with an agent that modulates a biological activity of DNA-PK.  
     
     
         15 . The method of  claim 14 , wherein the biological activity of DNA-PK is a kinase activity of DNA-PKcs.  
     
     
         16 . The method of  claim 15 , wherein said agent is an immunomodulatory nucleic acid molecule.  
     
     
         17 . A method of reducing cell death in an individual, comprising administering to an individual an effective amount of an agent that modulates a biological activity of DNA-PK.  
     
     
         18 . The method of  claim 17 , wherein the cell death is triggered by an ischemic condition.  
     
     
         19 . A method of reducing cell death in an organ, comprising contacting a cell of the organ with an effective amount of an agent that modulates a biological activity of DNA-PK.  
     
     
         20 . The method of  claim 19 , wherein the contacting is performed ex vivo.