Hdac inhibitors to treat charcot-marie-tooth disease

Abstract

The present application relates to diseases in the peripheral nervous system, particularly hereditary neuropathies, most particularly, Charcot-Marie-Tooth (CMT) disease. It is shown that this disease is associated with decreased acetylated tubulin levels, which can be overcome by inhibition of histone deacetylases (HDACs). Using HDAC inhibitors, it is shown herein that the symptoms of the CMT phenotype can be overcome both in vitro and in vivo. Also provided herein are two different mouse models of CMT disease.

1 . A method of treating Charcot-Marie-Tooth disease in a subject diagnosed therewith, the method comprising:
 administering a histone deacetylase (HDAC) inhibitor to the subject so as to treat the Charcot-Marie-Tooth disease.   
     
     
         2 . The method according to  claim 1 , wherein the Charcot-Marie-Tooth disease in the subject is axonal CMT or distal hereditary motor neuropathy. 
     
     
         3 . The method according to  claim 1 , wherein the Charcot-Marie-Tooth disease in the subject is characterized by at least one mutation in the HSPB1 gene or protein of the subject. 
     
     
         4 . The method according to  claim 3 , wherein the mutation in the HSPB1 gene or protein is a mutation in the alpha-crystallin domain of HSPB1. 
     
     
         5 . The method according to  claim 1 , wherein the HDAC inhibitor is an inhibitor of type II HDACs. 
     
     
         6 . The method according to  claim 5 , wherein the inhibitor is a selective inhibitor of type II HDACs. 
     
     
         7 . The method according to  claim 1 , wherein the HDAC inhibitor is an HDAC6 inhibitor. 
     
     
         8 . The method according to  claim 7 , wherein the HDAC6 inhibitor is a selective HDAC6 inhibitor. 
     
     
         9 . The method according to  claim 8 , wherein the selective HDAC6 inhibitor is selected from tubacin and tubastatin A. 
     
     
         10 . The method according to  claim 1 , wherein administration of the HDAC inhibitor results in improvement of at least one of the symptoms of Charcot-Marie-Tooth disease in the subject. 
     
     
         11 . A method of treating a subject determined to be suffering from Charcot-Marie-Tooth disease, the method comprising:
 inhibiting histone deacetylase(s) in the subject in order to treat the Charcot-Marie-Tooth disease.   
     
     
         12 . A transgenic non-human animal, comprising a mutation in the HSPB1 gene. 
     
     
         13 . The animal of  claim 12 , wherein the mutation is neuron-specific. 
     
     
         14 . The animal of  claim 12 , wherein the mutation is a point mutation. 
     
     
         15 . The animal of  claim 12 , which shows at least one of the symptoms of Charcot-Marie-Tooth disease observed in humans. 
     
     
         16 . The animal of  claim 14 , wherein the mutation is an S135F point mutation. 
     
     
         17 . The animal of  claim 14 , wherein the mutation is a P182L point mutation. 
     
     
         18 . The method according to  claim 4 , wherein the mutation in the HSPB1 gene or protein is a mutation residue S135. 
     
     
         19 . The method according to  claim 4 , wherein the mutation in the HSPB1 gene or protein is a mutation residue in the C-terminal tail. 
     
     
         20 . The method according to  claim 19 , wherein the mutation in the HSPB1 gene or protein is a mutation of residue P182. 
     
     
         21 . The method according to  claim 5 , wherein the HDAC inhibitor inhibits type IIb HDACs.