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 improving motor performance and electrophysiological parameters including Compound Muscle Action Potential (“CMAP”) amplitudes and Sensory Nerve Action Potential (“SNAP”) amplitudes in a subject suffering from Charcot-Marie-Tooth disease (“CMT”), wherein the CMT disease is characterized by at least one mutation in the HSPB1 gene or protein, the method comprising:
 increasing the subject's CMAP amplitude to at least 20 mV and the subject's SNAP amplitude to at least 10 μV or selectively inhibiting histone deacetylase 6; 
 wherein the subject's motor performance is improved. 
 
     
     
         2 . A method of improving motor performance in a subject suffering from Charcot-Marie-Tooth disease “CMT”, wherein the Charcot-Marie-Tooth disease is axonal CMT or distal hereditary motor neuropathy, the method comprising:
 increasing the subject's Compound Muscle Action Potential (“CMAP”) amplitude to at least 20 mV and the subject's Sensory Nerve Action Potential (“SNAP”) amplitude to at least 10 μV or selectively inhibiting histone deacetylase 6; 
 wherein the subject's motor performance is improved. 
 
     
     
         3 . (canceled) 
     
     
         4 . The method according to  claim 1 , wherein the mutation in the HSPB1 gene or protein is a mutation in the alpha-crystallin domain of HSPB1. 
     
     
         5 .- 8 . (canceled) 
     
     
         9 . The method according to  claim 1 , wherein the selective HDAC6 inhibitor is selected from the group consisting of tubacin and tubastatin A. 
     
     
         10 . (canceled) 
     
     
         11 . A method of improving steppage gait and electrophysiological parameters including Compound Muscle Action Potential (“CMAP”) amplitudes and Sensory Nerve Action Potential (“SNAP”) amplitudes in a subject determined to be suffering from Charcot-Marie-Tooth disease with impaired steppage gait, the method comprising:
 inhibiting histone deacetylase 6 (“HDAC6”) in the subject so as to increase the subject's CMAP amplitude to at least 20 mV and the subject's SNAP amplitude to at least 10 μV; 
 wherein administration of the selective HDAC6 inhibitor results in improvement of steppage gait in the subject. 
 
     
     
         12 . A method of improving steppage gait and electrophysiological parameters including CMAP amplitudes and SNAP amplitudes in a subject determined to be suffering from Charcot-Marie-Tooth disease with impaired steppage gait, wherein the Charcot-Marie-Tooth disease is characterized by at least one mutation in the HSPB1 gene or protein, the method comprising:
 administering a selective histone deacetylase 6 inhibitor to the subject in an amount that increases the subject's CMAP amplitude to at least 20 mV and the subject's SNAP amplitude to at least 10 μV;   wherein administration of the selective histone deacetylase 6 (“HDAC6”) inhibitor results in improvement of steppage gait in the subject.   
     
     
         13 . The method according to  claim 1 , wherein the mutation in HSPB1 is in S135. 
     
     
         14 . The method according to  claim 1 , wherein the mutation in HSPB1 is in the C-terminal tail. 
     
     
         15 . The method according to  claim 14 , wherein the mutation in HSPB1 is in P182. 
     
     
         16 . The method according to  claim 1 , wherein the subject's CMAP amplitude is increased to at least 40 mV and SNAP amplitude is increased to at least 20 μV. 
     
     
         17 . The method according to  claim 1 , wherein the subject's CMAP amplitude is increased to at least 60 mV and SNAP amplitude is increased to at least 30 μV.