Gene therapies for CMT neuropathies: from the bench to the clinic

Charcot-Marie-Tooth (CMT) neuropathies are rare, genetically heterogeneous and progressive diseases for which there are no approved treatments and their management remains mostly supportive and symptomatic. This review is intended to provide an update on recent developments in gene therapies for different CMT neuropathies.

Increasing knowledge of disease pathomechanisms underlying several CMT types has facilitated the development of promising viral and nonviral gene therapy approaches. Some of these therapies are currently approaching the crucial step of moving from the bench to the clinic, having passed the proof-of-concept stage in rodent models and some also in larger animals. However, questions of optimal delivery route and dose, off-target effects, and possible payload toxicity remain to be clarified for several of these approaches. Furthermore, limited resources, the rarity of most CMT subtypes, and issues of safety and regulatory requirements, create the need for consensus guidelines and optimal clinical trial design.

Promising gene therapies have been developed for several CMT neuropathies, with proof-of-principle demonstrated in relevant disease models. Advantages and drawbacks of each approach are discussed and remaining challenges are highlighted. Furthermore, we suggest important parameters that should be considered in order to successfully translate them into the clinic.