Long-term blinded placebo-controlled study of SNT-MC17/idebenone in the dystrophin deficient mdx mouse: cardiac protection and improved exercise performance
Long-term blinded placebo-controlled study of SNT-MC17/idebenone in the dystrophin deficient mdx mouse: cardiac protection and improved exercise performance
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DOI：
10.1093/eurheartj/ehn406
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发表时间：
2009-01-01
影响因子：
39.3
通讯作者：
Meier, Thomas
中科院分区：
文献类型：
--
作者：
Buyse, Gunnar M.;Van der Mieren, Gerry;Meier, Thomas
Duchenne肌营养不良症(DMD)是一种严重的、仍然无法治愈的疾病，心力衰竭是主要的死亡原因。确定一种疾病修正疗法可能需要早期启动和长期给药，但这种类型的治疗试验在人类身上并不明显。我们已经在DMD的MDX小鼠模型中进行了这样的试验，基于该药物改善线粒体呼吸链功能和减少氧化应激的潜力。在这项研究中，在MDX和野生型小鼠中，从4周到10个月期间给予200 mg/kg体重的SNT-MC17/艾地苯酮或安慰剂。所有评估者对小鼠类型和治疗组都是盲目的。艾地苯农治疗显著纠正了心脏舒张期功能障碍，防止了体内多巴酚丁胺负荷试验所致心泵衰竭的死亡，显著减少了心脏炎症和纤维化，并显著改善了MDX小鼠的自愿跑步能力。我们确定了一种新的潜在的治疗人类DMD的策略，因为SNT-MC17/艾地苯酮对Dstrophin缺乏的MDX小鼠具有心脏保护作用和改善运动能力。我们的数据还表明，MDX小鼠为长期受控的先于人类的治疗研究提供了独特的机会。
Duchenne muscular dystrophy (DMD) is a severe and still incurable disease, with heart failure as a leading 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.In this study, 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. Idebenone treatment significantly corrected cardiac diastolic dysfunction and prevented mortality from cardiac pump failure induced by dobutamine stress testing in vivo, significantly reduced cardiac inflammation and fibrosis, and significantly improved voluntary running performance in mdx mice.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. Our data also illustrate that the mdx mouse provides unique opportunities for long-term controlled prehuman therapeutic studies.