@article{9aa8349a8ea7496b9a11457914cd5971,
title = "Treatment with a triazole inhibitor of the mitochondrial permeability transition pore fully corrects the pathology of sapje zebrafish lacking dystrophin",
abstract = "High-throughput screening identified isoxazoles as potent but metabolically unstable inhibitors of the mitochondrial permeability transition pore (PTP). Here we have studied the effects of a metabolically stable triazole analog, TR001, which maintains the PTP inhibitory properties with an in vitro potency in the nanomolar range. We show that TR001 leads to recovery of muscle structure and function of sapje zebrafish, a severe model of Duchenne muscular dystrophy (DMD). PTP inhibition fully restores the otherwise defective respiration in vivo, allowing normal development of sapje individuals in spite of lack of dystrophin. About 80 % sapje zebrafish treated with TR001 are alive and normal at 18 days post fertilization (dpf), a point in time when not a single untreated sapje individual survives. Time to 50 % death of treated zebrafish increases from 5 to 28 dpf, a sizeable number of individuals becoming young adults in spite of the persistent lack of dystrophin expression. TR001 improves respiration of myoblasts and myotubes from DMD patients, suggesting that PTP-dependent dysfunction also occurs in the human disease and that mitochondrial therapy of DMD with PTP-inhibiting triazoles is a viable treatment option.",
keywords = "Duchenne muscular dystrophy, Mitochondria, Permeability transition, Respiration, Triazole",
author = "Anna Stocco and Natalia Smolina and Patrizia Sabatelli and Justina {\v S}ileikytė and Edoardo Artusi and Vincent Mouly and Michael Cohen and Michael Forte and Marco Schiavone and Paolo Bernardi",
note = "Funding Information: This work is in partial fulfillment of the requirements for the Ph.D. of Anna Stocco. Supported by Italian Telethon Foundation (GGP17092) and Fondation Leducq (16CVD04). We gratefully acknowledge the Zebrafish Facility at the Department of Biology, University of Padova and the platform for immortalization of human cells, Institut de Myologie, Sorbonne University, INSERM, Paris, particularly Anne Bigot and Kamel Mamchoui, and Association Fran?aise contre les Myopathies. Funding Information: This work is in partial fulfillment of the requirements for the Ph.D. of Anna Stocco. Supported by Italian Telethon Foundation ( GGP17092 ) and Fondation Leducq ( 16CVD04 ). We gratefully acknowledge the Zebrafish Facility at the Department of Biology, University of Padova and the platform for immortalization of human cells, Institut de Myologie, Sorbonne University, INSERM, Paris, particularly Anne Bigot and Kamel Mamchoui, and Association Fran{\c c}aise contre les Myopathies. Publisher Copyright: {\textcopyright} 2021 Copyright: Copyright 2021 Elsevier B.V., All rights reserved.",
year = "2021",
month = mar,
doi = "10.1016/j.phrs.2021.105421",
language = "English (US)",
volume = "165",
journal = "Pharmacological Research",
issn = "1043-6618",
publisher = "Academic Press Inc.",
}