{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,18]],"date-time":"2026-02-18T10:13:26Z","timestamp":1771409606437,"version":"3.50.1"},"reference-count":85,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,2,18]],"date-time":"2026-02-18T00:00:00Z","timestamp":1771372800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100014943","name":"Sarepta Therapeutics, Inc.","doi-asserted-by":"publisher","award":["GR001616"],"award-info":[{"award-number":["GR001616"]}],"id":[{"id":"10.13039\/100014943","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Mutations in the Mitofusin 2 (MFN2) gene cause Charcot\u2013Marie\u2013Tooth 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+\/\u2212 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+\/\u2212 mice received a 3 \u00d7 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+\/\u2212 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+\/\u2212 model of CMT2A, providing further support for the translational potential of this surrogate gene therapy approach to CMT2A patients.<\/jats:p>","DOI":"10.3390\/ijms27041942","type":"journal-article","created":{"date-parts":[[2026,2,18]],"date-time":"2026-02-18T09:22:46Z","timestamp":1771406566000},"page":"1942","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["AAVrh74.tMCK.NT-3 Surrogate Gene Therapy in a Mouse Model of CMT2A"],"prefix":"10.3390","volume":"27","author":[{"given":"Burcak","family":"Ozes","sequence":"first","affiliation":[{"name":"Center for Gene Therapy, The Abigail Wexner Research Institute, Nationwide Children\u2019s Hospital, 700 Children\u2019s Drive, Columbus, OH 43205, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lingying","family":"Tong","sequence":"additional","affiliation":[{"name":"Center for Gene Therapy, The Abigail Wexner Research Institute, Nationwide Children\u2019s Hospital, 700 Children\u2019s Drive, Columbus, OH 43205, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kyle","family":"Moss","sequence":"additional","affiliation":[{"name":"Center for Gene Therapy, The Abigail Wexner Research Institute, Nationwide Children\u2019s Hospital, 700 Children\u2019s Drive, Columbus, OH 43205, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9136-7128","authenticated-orcid":false,"given":"Morgan","family":"Myers","sequence":"additional","affiliation":[{"name":"Center for Gene Therapy, The Abigail Wexner Research Institute, Nationwide Children\u2019s Hospital, 700 Children\u2019s Drive, Columbus, OH 43205, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Israel","family":"Ndengabaganizi","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Nationwide Children\u2019s Hospital, Columbus, OH 43205, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2974-3943","authenticated-orcid":false,"given":"Zarife","family":"Sahenk","sequence":"additional","affiliation":[{"name":"Center for Gene Therapy, The Abigail Wexner Research Institute, Nationwide Children\u2019s Hospital, 700 Children\u2019s Drive, Columbus, OH 43205, USA"},{"name":"Department of Pathology and Laboratory Medicine, Nationwide Children\u2019s Hospital, Columbus, OH 43205, USA"},{"name":"Department of Pediatrics and Neurology, Nationwide Children\u2019s Hospital and The Ohio State University, Columbus, OH 43205, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"645","DOI":"10.1001\/jamaneurol.2016.0171","article-title":"Phenotypic Variability of Childhood Charcot-Marie-Tooth Disease","volume":"73","author":"Cornett","year":"2016","journal-title":"JAMA Neurol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1016\/B978-0-323-98818-6.00009-1","article-title":"Hereditary neuropathy","volume":"Volume 195","author":"Pisciotta","year":"2023","journal-title":"Handbook of Clinical Neurology"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"3144","DOI":"10.1093\/brain\/awae064","article-title":"Whole genome sequencing increases the diagnostic rate in Charcot-Marie-Tooth disease","volume":"147","author":"Record","year":"2024","journal-title":"Brain"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1038\/ng1341","article-title":"Mutations in the mitochondrial GTPase mitofusin 2 cause Charcot-Marie-Tooth neuropathy type 2A","volume":"36","author":"Zuchner","year":"2004","journal-title":"Nat. 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