HDAC inhibitors to treat charcot-marie-tooth disease

摘要

The disclosure relates to diseases in the peripheral nervous system, particularly hereditary neuropathies, such as 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.

主权项

1. A method of improving steppage gait in a subject suffering from Charcot-Marie-Tooth disease with impaired steppage gait, wherein the Charcot-Marie-Tooth disease is characterized by a mutation in the alpha-crystallin domain of 27 kDa small heat-shock protein 1 (HSPB1), the method comprising:
administering 25 mg/kg bodyweight of tubastatin A to the subject in need thereof to increase the electrophysiological parameters including compound muscle action potential (CMAP) amplitudes and sensory nerve action potential (SNAP) amplitudes, thereby improving steppage gait in the subject.