Year: 2026
Type: article
Abstract: Mutations in the Mitofusin 2 (MFN2) 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 the Mfn2+/− mouse 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-old Mfn2+/− mice received a 3 × 1011 vector genome dose of AAVrh74.tMCK.NT-3 intramuscularly, and functional, electrophysiological, and histological outcomes were assessed six months post-treatment. NT-3 gene therapy in Mfn2+/− mice 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 the Mfn2+/− model of CMT2A, providing further support for the translational potential of this surrogate gene therapy approach to CMT2A patients.
DOI: 10.3390/ijms27041942
Authors: Burcak Ozes, Lingying Tong, Kyle Moss, Morgan Myers, Israel Ndengabaganizi, Zarife Sahenk
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,499
Funder: Sarepta Therapeutics
Award: G1271337132
OpenAlex ID: W7130413754