@article{35f7115a8ea34cf7b000cf0e8388c15d,
title = "Burst mitofusin activation reverses neuromuscular dysfunction in murine cmt2a",
abstract = "Charcot-Marie-Tooth disease type 2A (CMT2A) is an untreatable childhood peripheral neuropathy caused by mutations of the mitochondrial fusion protein, mitofusin (MFN) 2. Here, pharmacological activation of endogenous normal mitofusins overcame dominant inhibitory effects of CMT2A mutants in reprogrammed human patient motor neurons, reversing hallmark mitochondrial stasis and fragmentation independent of causal MFN2 mutation. In mice expressing human MFN2 T105M, intermittent mitofusin activation with a small molecule, MiM111, normalized CMT2A neuromuscular dysfunction, reversed pre-treatment axon and skeletal myocyte atrophy, and enhanced axon regrowth by increasing mitochondrial transport within peripheral axons and promoting in vivo mitochondrial localization to neuromuscular junctional synapses. MiM111-treated MFN2 T105M mouse neurons exhibited accelerated primary outgrowth and greater post-axotomy regrowth, linked to enhanced mitochondrial motility. MiM111 is the first pre-clinical candidate for CMT2A.",
author = "Antonietta Franco and Xiawei Dang and Walton, {Emily K.} and Ho, {Joshua N.} and Barbara Zablocka and Cindy Ly and Miller, {Timothy M.} and Baloh, {Robert H.} and Shy, {Michael E.} and Yoo, {Andrew S.} and Dorn, {Gerald W.}",
note = "Funding Information: We gratefully acknowledge helpful discussions with Drs. P. Needleman, P.V. Halushka, and D. Mochly-Rosen, the specialized assistance of L. Zhang., and C. Cantoni for flow cytometry analysis. Funding: Supported by NIH R35HL135736, R41NS113642, R41NS115184, Research Grant 628906 from the Muscular Dystrophy Association (GWD), and a McDonnell Center for Cellular and Molecular Neurobiology Postdoctoral Fellowship (AF). G.W.D. is the Philip and Sima K. Needleman-endowed Professor and a Scholar-Innovator awardee of the Harrington Discovery Institute, Videoconfocal and electron microscopy studies were performed at the Washington University Center for Cellular Imaging (WUCCI) supported by the Washington University School of Medicine, the Children{\textquoteright}s Discovery Institute of Washington University (CDI-COREs 2015-515 and 2019-813) and the Foundation for Barnes-Jewish Hospital (3770 and 4672). Competing interests: G.W.D. is an inventor on patent applications PCT/US18/028514 submitted by Washington University and PCT/US19/46356 submitted by Mitochondria Emotion, Inc that cover the use of small molecule mitofusin agonists to treat chronic neurodegenerative diseases, and is a founder of Mitochondria in Motion, Inc., a Saint Louis based biotech R&D company focused on enhancing mitochondrial trafficking and fitness in neurodegenerative diseases. The other authors declare no competing interests. Data and materials availability: All data are available in the manuscript or the supplementary material. Studies using MiM111 were performed under terms of an MTA between Mitochondria in Motion, Inc. and Washington University. Funding Information: Supported by NIH R35HL135736, R41NS113642, R41NS115184, Research Grant 628906 from the Muscular Dystrophy Association (GWD), and a McDonnell Center for Cellular and Molecular Neurobiology Postdoctoral Fellowship (AF). G.W.D. is the Philip and Sima K. Needleman-endowed Professor and a Scholar-Innovator awardee of the Harrington Discovery Institute, Videoconfocal and electron microscopy studies were performed at the Washington University Center for Cellular Imaging (WUCCI) supported by the Washington University School of Medicine, the Children?s Discovery Institute of Washington University (CDI-COREs 2015-515 and 2019-813) and the Foundation for Barnes-Jewish Hospital (3770 and 4672). Competing interests: G.W.D. is an inventor on patent applications PCT/US18/028514 submitted by Washington University and PCT/US19/46356 submitted by Mitochondria Emotion, Inc that cover the use of small molecule mitofusin agonists to treat chronic neurodegenerative diseases, and is a founder of Mitochondria in Motion, Inc., a Saint Louis based biotech R&D company focused on enhancing mitochondrial trafficking and fitness in neurodegenerative diseases. The other authors declare no competing interests. Data and materials availability: All data are available in the manuscript or the supplementary material. Studies using MiM111 were performed under terms of an MTA between Mitochondria in Motion, Inc. and Washington University. Publisher Copyright: {\textcopyright} 2020, eLife Sciences Publications Ltd. All rights reserved.",
year = "2020",
month = oct,
doi = "10.7554/eLife.61119",
language = "English",
volume = "9",
pages = "1--42",
journal = "eLife",
issn = "2050-084X",
}