AAVrh74.tMCK.NT-3 Surrogate Gene Therapy in a Mouse Model of CMT2A.

Abstract

Mutations in the() gene cause Charcot-Marie-Tooth type 2A (CMT2A). Neurotrophin 3 (NT-3) is an autocrine factor that supports Schwann cell survival and differentiation, axon regeneration and myelination, neuromuscular junction (NMJ) integrity, and mitochondrial function. In this study, we assessed the efficacy of NT-3 gene therapy using the AAVrh74 serotype in themouse model for CMT2A. Although haploinsufficiency is not reported in CMT2A patients, our model shows some features of CMT2A, including axonal atrophy, muscle atrophy, length-dependent axon loss, and abnormal mitochondria, in muscle in the enzyme histochemistry. Eight-month-oldmice received a 3 × 10vector genome dose of AAVrh74.tMCK.NT-3 intramuscularly, and functional, electrophysiological, and histological outcomes were assessed six months post-treatment. NT-3 gene therapy inmice significantly improved grip strength and rotarod performance, and ameliorated electrophysiological abnormalities and NMJ denervation in lumbrical muscles. Additionally, our therapeutic approach improved muscle histopathology with reductions in mitochondrial abnormalities and oxidative stress. NT-3 further remodeled carbohydrate metabolism in muscle. Our study indicated that AAV.NT-3 gene therapy has a disease-modifying effect in themodel of CMT2A, providing further support for the translational potential of this surrogate gene therapy approach to CMT2A patients.