Countering sympathetic vasoconstriction during skeletal muscle exercise as an adjuvant therapy for DMD

Duchene肌营养不良症（DMD）是一种无法治愈的神经肌肉疾病，其特征在于 肌肉迅速退化，线粒体和血管受损，导致过早丧失 和死亡率。新兴的疾病修饰疗法旨在部分恢复 缺失的肌膜蛋白抗肌萎缩蛋白（对稳定和分子水平的 信令）。虽然他们预计将改善肌肉功能和日常活动的男孩， DMD，大多数不是为了纠正血管损伤（因为它们不能恢复nNO 在运动期间和运动后促进血管舒张所需的信号传导）。因此，活跃的肌肉 的DMD男孩接受这些治疗将有不充分的灌注，造成损伤， 疲劳，尽管部分肌营养不良蛋白替代。他达拉非，一种FDA批准的血管扩张药物， 有潜力填补这一治疗空白;临床前和临床数据显示，它改善了灌注、疲劳 和DMD小鼠的损伤，以及DMD男孩的运动后血流量。然而，一个阶段 3项评估DMD患者长期他达拉非治疗的临床试验未能使6分钟步行获益 测试（主要结局），尽管改善了手臂功能。由于在初级治疗中缺乏疗效， 结果，他达拉非已被视为DMD治疗药物。我们假设， 对于可变的动态下降率（可能影响主要结局）和他达拉非 参与（需要充分使用腿部肌肉）是其缺乏功效的原因。我们 一项随机、安慰剂对照的探索性临床试验将解决这些局限性， 他达拉非联合结构性运动可改善肌肉的概念证明 DMD的病理生理学和功能。我们的初步数据显示他达拉非可以挽救活性- DMD男孩（7-12岁）的依赖性血流缺陷。我们的方法是先筛选 一次给药后的药物反应性（肌肉氧合增加）。响应者将 随机接受6个月他达拉非或安慰剂干预，联合结构化周期 运动训练（以确保定期的肌肉激活）。我们将量化干预对 血管损伤和肌肉病理生理学（炎症、脂肪积累、线粒体 功能障碍）、运动性疲劳和骑车性能。我们的研究结果预计将提供1） 对最有可能从他达拉非辅助治疗中获益的DMD患者进行分层的标准; 2） 证明了药物影响和运动训练在DMD中的强大协同作用。的对齐甲 这一R21 FOA，因为它将提供初步数据，以促进一个强大的，长期的临床试验， 血管扩张药物和运动训练，有或没有基因替代疗法，将 导致DMD治疗临床上有意义的改善。

Duchene muscular dystrophy (DMD) is an incurable neuromuscular disease characterized by rapid muscle deterioration, mitochondrial and vascular impairments, resulting in premature loss of ambulation and mortality. Emerging disease-modifying therapeutics aim to partially restore levels of the missing sarcolemma protein dystrophin (critical for stabilizing and molecular signaling). Although they are expected to improve muscle function and daily activity in boys with DMD, most are not designed to correct the vascular impairment (since they do not restore nNOs signaling which is needed to promote vasodilation during and after exercise). Thus, active muscle of DMD boys treated with these therapeutics will have inadequate perfusion, causing injury and fatigue despite partial dystrophin replacement. Tadalafil, an FDA-approved vasodilator drug has potential to fill this therapeutic void; preclinical and clinical data show it improves perfusion, fatigue and injury in mice with DMD, and post-exercise blood flow in boys with DMD. However, a phase 3 clinical trial assessing long-term tadalafil treatment in DMD failed to benefit the 6 minute walk test (primary outcome), despite improved arm function. Based on lack of efficacy in the primary outcome, tadalafil has been dismissed as a DMD therapeutic. We postulate that failure to account for variable rates of ambulatory decline (which can affect the primary outcome) and tadalafil engagement (which requires sufficient use of leg muscles) account for its lack of efficacy. Our randomized, placebo-controlled Exploratory Clinical Trial will address these limitations and seek proof of concept that tadalafil combined with structured exercise will improve muscle pathophysiology and function in DMD. Our preliminary data show tadalafil can rescue activity- dependent blood flow deficits in boys with DMD (aged 7-12 years). Our approach is to first screen for drug responsiveness (increase in muscle oxygenation) after one dose. Those responsive will be randomized to a 6-month intervention of tadalafil or placebo, combined with structured cycle exercise training (to ensure regular muscle activation). We will quantify the intervention impact on vascular impairment and muscle pathophysiology (inflammation, fat accumulation, mitochondrial dysfunction), exertional fatigue and cycling performance. Our findings are expected to provide 1) criteria to stratify DMD patients most likely to benefit from tadalafil as adjuvant therapy and 2) demonstrate a powerful synergy between drug impact and exercise training in DMD. It aligns with this R21 FOA as it will provide preliminary data to foster a robust, longer-term clinical trial using vasodilator drugs and exercise training, with and without gene replacement therapies, that will lead to clinically meaningful improvements in DMD treatment.