Treatment of parkinson's disease and other conditions caused or mediated by senescent astrocytes using small molecule senolytic agents

Abstract

This invention establishes a new paradigm for treatment of Parkinson's disease (PD) by eliminating senescent cells that reside in or around the site of the disease pathophysiology. Exposure of test subjects to the herbicide paraquat (PQ) increases the risk for developing Parkinson's disease. The data in this disclosure show that PQ induces a senescence arrest and SASP in astrocytes, in culture and in vivo in mice, and senescent cell markers were present in astrocytes in midbrain tissue from PD patients. In a transgenic mouse model, senescent cell ablation protected against PQ-induced PD-like neuropathology. Removal of senescent cells from affected sites using small molecule agents that specifically target senescent cells can help prevent or ameliorate signs and symptoms of the disease.

The invention claimed is: 
     
         1 . A method of preventing or treating Parkinson's disease in a subject in need thereof, comprising removing senescent cells in the brain of the subject, whereby at least one sign or symptom of the disease is decreased in severity. 
     
     
         2 . The method of either  claim 1 , wherein the senescent cells are astrocytes. 
     
     
         3 . A method of preventing or treating Parkinson's disease in a subject in need thereof, comprising contacting senescent cells in the brain with a senolytic agent that is a means for inhibiting Bcl-2 or Bcl-xL. 
     
     
         4 . The method of  claim 3 , wherein the means for inhibiting Bcl-2 or Bcl-xL is selected from WEHI 539, A 1155463, ABT-737, and ABT-263 (Navitoclax). 
     
     
         5 . The method of  claim 3 , wherein the means for inhibiting Bcl-2 or Bcl-xL has the structure shown in Formula II: 
       
         
           
           
               
               
           
         
         wherein X 3  is Cl or F;
 X 4  is azepan-1-yl, morpholin-4-yl, 1,4-oxazepan-4-yl, pyrrolidin-1-yl, N(CH 3 ) 2 , N(CH 3 )(CH(CH 3 ) 2 ), 7-azabicyclo[2.2.1]heptan-1-yl or 2-oxa-5-azabicyclo[2.2.1]hept-5-yl, and R 0  is 
 
       
       
         
           
           
               
               
           
         
         wherein X 5  is CH 2 , C(CH 3 ) 2 , or CH 2 CH 2 ; X 6  and X 7  are both hydrogen or are both methyl; and X 8  is F, Cl, Br or I; or
 X 4  is azepan-1-yl, morpholin-4-yl, pyrrolidin-1-yl, N(CH 3 )(CH(CH 3 ) 2 ) or 7-azabicyclo[2.2.1]heptan-1-yl, and R 0  is 
 
       
       
         
           
           
               
               
           
         
       
       or
 X 4  is N(CH 3 ) 2  or morpholin-4-yl, and R 0  is 
 
       
         
           
           
               
               
           
         
       
     
     
         6 . The method of  claim 3 , wherein the means for inhibiting Bcl-2 or Bcl-xL is ABT-263 (Navitoclax). 
     
     
         7 . The method of  claim 3 , wherein the senolytic agent is administered to the subject in a therapeutically effective course of therapy that includes a period of treatment followed by a non-treatment interval of at least two weeks. 
     
     
         8 . The method of  claim 7 , wherein the non-treatment interval is at least one month, during which the subject is relieved of one or more signs or symptoms of the Parkinson's disease. 
     
     
         9 . The method of  claim 7 , wherein a single dose of the senolytic agent is administered during the period of treatment. 
     
     
         10 . A unit dose of a pharmaceutical composition for treating Parkinson's disease in a subject in need thereof;
 wherein the composition contains a senolytic agent which is a means for inhibiting Bcl-2 or Bcl-xL;   wherein the senolytic agent is part of a formulation that is suitable for administration to neural tissue; and   wherein the formulation of the composition and the amount of the senolytic agent in the unit dose configure the unit dose to be effective in treating Parkinson's disease by removing senescent cells from the tissue, thereby decreasing the severity of one or more signs or symptoms of the disease without causing adverse effects when administered as a single dose.   
     
     
         11 . The unit dose according to  claim 10 , wherein the means for inhibiting Bcl-2 or Bcl-xL is selected from WEHI 539, A 1155463, ABT-737, and ABT-263 (Navitoclax). 
     
     
         12 . The unit dose according to  claim 10 , wherein the means for inhibiting Bcl-2 or Bcl-xL has the structure shown in Formula II: 
       
         
           
           
               
               
           
         
         wherein X 3  is Cl or F;
 X 4  is azepan-1-yl, morpholin-4-yl, 1,4-oxazepan-4-yl, pyrrolidin-1-yl, N(CH 3 ) 2 , N(CH 3 )(CH(CH 3 ) 2 ), 7-azabicyclo[2.2.1]heptan-1-yl or 2-oxa-5-azabicyclo[2.2.1]hept-5-yl, and R 0  is 
 
       
       
         
           
           
               
               
           
         
         wherein X 5  is CH 2 , C(CH 3 ) 2 , or CH 2 CH 2 ; X 6  and X 7  are both hydrogen or are both methyl; and X 8  is F, Cl, Br or I; or
 X 4  is azepan-1-yl, morpholin-4-yl, pyrrolidin-1-yl, N(CH 3 )(CH(CH 3 ) 2 ) or 7-azabicyclo[2.2.1]heptan-1-yl, and R 0  is 
 
       
       
         
           
           
               
               
           
         
       
       or
 X 4  is N(CH 3 ) 2  or morpholin-4-yl, and R 0  is 
 
       
         
           
           
               
               
           
         
       
     
     
         13 . The unit dose according to  claim 10 , wherein the means for inhibiting Bcl-2 or Bcl-xL is ABT-263 (Navitoclax). 
     
     
         14 . The unit dose according to  claim 10 , packaged together with a plurality of other such unit doses for retail sale. 
     
     
         15 . The unit dose according to  claim 10 , packaged with an informational insert describing the use and attendant benefits of the unit dose for treating Parkinson's disease.