AAV9-mediated gene replacement strategy for the treatment of Charcot-Marie-Tooth type 4B1 and B2 neuropathies with aberrant myelin

Charcot-Marie-Tooth (CMT) neuropathies represent a broad group of inherited disorders with a prevalence of 1 on 2500 individuals. CMTs are generally characterized by progressive muscular atrophy and weakness, with an age at onset usually comprised between the first and the second decade of life. Unfortunately, despite their frequency and relevance, no therapies are available to date for any CMT form. Among CMT neuropathies, CMT4B are very severe demyelinating neuropathies with childhood onset, characterized by myelin outfoldings, a form of aberrant myelin in the nerve that degenerate causing axonal problems. CMT4B1 is caused by loss of the MTMR2 (Myotubularin-related 2) phosphatase that dephosphorylates phospholipids, important regulators of membrane trafficking, which is a key process in Schwann cells, the glial cells forming myelin in the peripheral nervous system. CMT4B2 neuropathy is clinically very similar to CMT4B1 and is caused by loss of MTMR13, which is catalytically inactive but interacts with MTMR2 to regulate its function. Thanks to the Telethon support over many years, we identified the MTMR2 and MTMR13 genes, we generated animal and cellular models of these neuropathies, which have been instrumental to study the pathophysiology of this neuropathy. In this project, we aim at generating proof-of-concept of efficacy of gene replacement strategies for the therapy of these severe forms of neuropathies. Gene therapy has emerged as a valid and effective strategy to cure severe neuromuscular disorders and gained recent attention for CMT neuropathies given the promising data obtained at preclinical level.