I.05 Preclinical testing of emerging therapies for inherited peripheral neuropathies

Abstract

Charcot-Marie-Tooth disease (CMT) is a clinically and genetically heterogeneous collection of inherited peripheral neuropathies caused by mutations in at least one hundred genes. There are currently no approved treatments for any form of CMT, and the heterogeneity of CMT makes it unlikely that a single therapeutic strategy will prove efficacious across all disease subtypes. Gene therapies and related methods offer bespoke approaches for specific CMT subtypes, but there are also common pathways perturbed across multiple forms of CMT that may provide therapeutic targets. These pathways include 1) Enhancing axonal transport by inhibiting HDAC6 to increase acetylation of axonal alpha-Tubulin. 2) Inhibiting axon loss by targeting SARM1, a key effector of the active program of Wallerian and other forms of axon degeneration. And 3) Targeting cell stress pathways, both positively and negatively, to treat demyelinating and axonal forms of CMT. Preclinical studies in mouse models of CMT highlight both successes and failures in these approaches, but therapeutic strategies that may apply across multiple forms of CMT are emerging.