Compositions and Methods for the Treatment of Diseases Associated with Aberrant Cilia Assembly and Regulation

Abstract

Compositions and methods are provided for identifying agents which have efficacy for the treatment of disorders related to aberrant cilial structure and function, including polycystic kidney disease.

1 . A method for identifying agents which modulate calmodulin-Aurora A complex formation having efficacy for the treatment of polycystic kidney disease (PKD), comprising:
 a) providing kidney cells which express Aurora A and calmodulin and incubating cells in the presence and absence of said agent and in the presence of a molecule which induces release of Ca 2+ ;   b) determining the extent said agent disrupts calmodulin-Aurora A complex formation following release of calcium, agents which disrupt complex formation having efficacy for the treatment of PKD.   
     
     
         2 . The method of  claim 1 , wherein said agent inhibits activation of aurora A kinase. 
     
     
         3 . The method of  claim 2 , wherein said aurora A kinase inhibitor is selected from the group consisting of siRNA which specifically down modulate Aurora A expression, C1368, PHA-680632, MK-0457, ZM447439, MLN 8237, MLN 8054, VX-680 and hesparadin. 
     
     
         4 . The method of  claim 1 , comprising determining whether said agent disrupts aurora A binding to PC2. 
     
     
         5 . The method of  claim 1 , comprising determining whether said agent alters cellular localization of PC2. 
     
     
         6 . The method of  claim 1 , comprising determining whether said agent alters Aurora A phosphorylation of PC2. 
     
     
         7 . A method for inhibiting progression of polycystic kidney disease in a patient in need thereof, comprising administration of an effective amount of an aurora kinase inhibitor, said inhibitor being effective to inhibit cyst formation in the kidney. 
     
     
         8 . The method of  claim 7 , wherein said kinase inhibitor is effective to inhbit aurora kinase A and aurora kinase B. 
     
     
         9 . The method of  claim 7 , wherein said kinase inhibitor is effective to inhibit aurora kinase A or aurora kinase B. 
     
     
         10 . The method of  claim 7 , wherein said aurora kinase inhibitor is selected from the group consisting of siRNA which specifically down modulate Aurora A expression, C1368, PHA-680632, MK-0457, ZM447439, MLN 8237, VX-680 and hesparadin.