Compositions and Methods for the Treatment of Prader-Willi Syndrome

Abstract

The invention provides pharmaceutical compositions and methods of use thereof for treating Prader-Willi syndrome. More specifically, the invention provides pharmaceutical compositions that when administered inhibit the G9a driven methylation of histone H3 lysine 9.

1 . A method of activating at least one maternal copy of candidate Prader-Willi syndrome (PWS) associated genes, the method comprising inhibiting G9a activity by administering an interfering molecule. 
     
     
         2 . The method according to  claim 1 , wherein inhibiting G9a activity comprises inhibiting the methylation of the histone H3 protein. 
     
     
         3 . The method according to  claim 2 , wherein the methylation of histone H3 at lysine 9 (H3K9) is inhibited. 
     
     
         4 . The method according to  claim 3 , wherein inhibiting the methylation of H3K9 comprises a selective reduction of dimethylation of histone 3 lysine 9. 
     
     
         5 . The method according to  claim 1 , wherein the candidate PWS associated genes are located on the 15q11-q13 region between the MAGEL2 and UBE3A genes. 
     
     
         6 . The method according to  claim 1 , wherein the candidate PWS associated genes comprise MAGEL2, NDN, SNRPN and SnoRNAs genes. 
     
     
         7 . The method according to  claim 6 , wherein the SnoRNAs genes comprise SNORD116 and SNORD115. 
     
     
         8 . The method according to  claim 1 , wherein the interfering molecule is a G9a inhibitor. 
     
     
         9 . The method according to  claim 8 , wherein the G9a inhibitor is UNC617, UNC618, UNC0638, UNC0642, or any combination thereof. 
     
     
         10 . The method according to  claim 1 , wherein the activation of at least one maternal copy of candidate PWS associated genes is carried out in a mammalian subject in need thereof. 
     
     
         11 . The method according to  claim 10 , wherein the subject is a human. 
     
     
         12 . A method of treating Prader-Willi syndrome (PWS) in a subject in need thereof, the method comprising unsilencing candidate PWS associated genes on the maternal chromosome by administering a therapeutically effective amount of an interfering molecule. 
     
     
         13 . The method of  claim 12 , wherein administering a therapeutically effective amount of an interfering molecule reduces the methylation of H3K9. 
     
     
         14 . The method according to  claim 12 , wherein the interfering molecule is a G9a inhibitor. 
     
     
         15 . The method according to  claim 14 , wherein the G9a inhibitor is UNC617, UNC618, UNC0638, UNC0642, or any combination thereof. 
     
     
         16 . The method according to  claim 12 , wherein the therapeutically effective amount of an interfering molecule activates at least one gene within the PWS critical region or the PWS-IC-controlled region. 
     
     
         17 . The method of  claim 16 , wherein the at least one gene within the PWS critical region that is activated is SNORD116. 
     
     
         18 . The method according to  claim 12 , wherein the subject is a mammal. 
     
     
         19 . The method according to  claim 17 , wherein the subject is a human. 
     
     
         20 .- 24 . (canceled) 
     
     
         25 . The method according to  claim 1 , wherein the method further comprises inhibiting DNA methylation of the PWS associated genes. 
     
     
         26 . (canceled) 
     
     
         27 . The method according to  claim 1 , wherein the interfering molecule is of Formula I: 
       
         
           
           
               
               
           
         
         wherein 
         R 1  is —C 1 -C 8  alkyl, —C 3 -C 8  cycloalkyl, or —C 3 -C 8  heterocycle comprising 1-3 heteroatoms, each of which may be optionally substituted with one or more halogens; 
         each X is independently —CH— or —N—; 
         R 2  is —C 3 -C 8  cycloalkyl or —C 3 -C 8  heterocycle comprising 1-3 heteroatoms, each of which may be optionally substituted with one or more alkyl groups, with one or more halogens, or with a combination thereof; 
         R 3  is —H, —C 1 -C 8  alkyl, halogen, —CN, —CF 3 , —NO 2  or —OR 5 ;
 wherein R 5  is —C 1 -C 8  alkyl; and 
 
         m and n are each independently 1, 2, 3, 4, or 5. 
       
     
     
         28 . The method according to  claim 1 , wherein the interfering molecule is of Formula II: 
       
         
           
           
               
               
           
         
         wherein R 2  is —C 3 -C 8  cycloalkyl or —C 3 -C 8  heterocycle comprising 1-3 heteroatoms, each of which may be optionally substituted with one or more alkyl groups, with one or more halogens, or with a combination thereof.