Résumé :
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Background - Duchenne muscular dystrophy (DMD) is a severe and still incurable disease, with heart failure as a major cause of death. The identification of a disease-modifying therapy may require early-initiated and long-term administration, but such type of therapeutic trial is not evident in humans. We have performed such a trial of SNT-MC17/idebenone in the mdx mouse model of DMD, based on the drug’s potential to improve mitochondrial respiratory chain function and reduce oxidative stress. The mouse model allowed presymptomatic initiation and veritable long-term administration of treatment, as well as the use of gold standard in vivo invasive pressure-volume measurements for assessing cardiac contractility. Methods & Results - 200 mg/kg bodyweight of either SNT-MC17/idebenone or placebo was given from age 4 weeks until 10 months in mdx and wild-type mice. All evaluators were blinded to mouse type and treatment groups. Compared to wild-type mice, placebo-treated mdx mice showed cardiac hypertrophy, diastolic dysfunction, reduced contractile reserve with systolic failure and 58% mortality during low-dose dobutamine stress, cardiac inflammation and fibrosis, and reduced voluntary wheel running performance. Idebenone treatment significantly corrected cardiac diastolic dysfunction and significantly prevented mortality from cardiac pump failure induced by dobutamine stress testing, significantly reduced cardiac inflammation and fibrosis, and significantly improved voluntary running performance in mdx mice. Conclusions - We have identified a novel potential therapeutic strategy for human DMD, as SNT-MC17/idebenone was cardioprotective and improved exercise performance in the dystrophin-deficient mdx mouse. These animal data encourage investigation of SNT-MC17/idebenone in human DMD. Our data also illustrate that the mdx mouse provides unique opportunities for long-term controlled prehuman therapeutic studies.
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