Charcot-Marie-Tooth neuropathies: current gene therapy advances and the route towards translation.

Abstract

Charcot-Marie-Tooth (CMT) neuropathies are a group of genetically and phenotypically heterogeneous disorders that predominantly affect the peripheral nervous system. Unravelling the genetic and molecular mechanisms, as well as the cellular effects of CMT mutations has facilitated the development of promising gene therapy approaches. Proposed gene therapy treatments for CMTs include virally or non-virally mediated gene replacement, addition, silencing, modification and editing of genetic material. For most CMT neuropathies gene- and disease- and even mutation- specific therapy approaches targeting the neuronal axon or myelinating Schwann cells may be needed, due to the diversity of underlying cellular and molecular-genetic mechanisms. The efficiency of gene therapies to improve the disease phenotype has been tested mostly in vitro and in in vivo rodent models that reproduce different molecular and pathological aspects of CMT neuropathies. In the next stage, bigger animal models, in particular non-human-primates, provide important insights into the translatability of the proposed administration and dosing, demonstrating scale-up potential and safety. The path towards clinical trials is faced with further challenges, but is becoming increasingly feasible owing to the progress and knowledge gained from clinical applications of gene therapies for other neurological disorders, as well as the emergence of sensitive outcome measures and biomarkers in patients with CMT neuropathies. This article is protected by copyright. All rights reserved.