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

骨骼肌运动期间对抗交感血管收缩作为 DMD 的辅助治疗

基本信息

批准号：
10735090
负责人：
Tanja Taivassalo
金额：
$ 53.68万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-15 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10735090
关键词：
Adjuvant Therapy Aerobic Exercise Affect Age Binding Biometry Blood Vessels Blood flow Clinical Clinical Data Clinical Trials Controlled Clinical Trials Data Disease Disease Progression Dose Drug Combinations Drug Screening Drug Targeting Duchenne muscular dystrophy Dystrophin Ensure Exercise Exercise Physiology Exercise Tolerance Exertion FDA approved Failure Fatigue Fatty acid glycerol esters Fostering Functional disorder Future Genes Goals Human Image Impairment Inflammation Injury Intervention Ischemia Leg Metabolic Mitochondria Molecular Mus Muscle Muscle Fatigue Muscle function Muscular Atrophy Muscular Dystrophies Myocardium Negative Finding Neuromuscular Diseases Newly Diagnosed Nitric Oxide Synthase Type I Outcome Patient-Focused Outcomes Patients Performance Perfusion Pharmaceutical Preparations Phase III Clinical Trials Physical activity Physiological Placebo Control Placebos Proteins Quality of life Randomized Recommendation Recovery Regulation Replacement Therapy Research Resistance Sarcolemma Severity of illness Signal Transduction Skeletal Muscle Structure Testing Therapeutic Training Treatment Efficacy Treatment outcome United States Vasodilation Vasodilator Agents Walking active lifestyle advanced disease age stratification aged arm arm function boys clinical care cohort exercise capacity exercise training exon skipping gene replacement therapy gene therapy improved inhibitor interpatient variability male mdx mouse mitochondrial dysfunction mortality pre-clinical premature primary outcome response synergism tadalafil therapy development treatment optimization vasoconstriction

项目摘要

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.

Duchene肌肉营养不良（DMD）是一种无法治愈的神经肌肉疾病，其特征是快速肌肉恶化，线粒体和血管障碍，导致过早损失行动和死亡率。新兴疾病改良治疗剂旨在部分恢复丢失的肌膜蛋白肌营养不良蛋白的水平（对于稳定和分子至关重要信号）。尽管预计他们将改善患有男孩的肌肉功能和日常活动 DMD，大多数并非旨在纠正血管障碍（因为它们不恢复nnos 在运动期间和之后促进血管舒张所需的信号传导）。因此，活跃的肌肉接受这些治疗剂治疗的DMD男孩的灌注不足，造成伤害和疲劳，尽管置换了部分肌营养素。 Tadalafil，一种由FDA批准的血管扩张剂药物已有填补这种治疗空隙的潜力；临床前和临床数据表明，它改善了灌注，疲劳 DMD的小鼠和小鼠的损伤，以及在患有DMD的男孩的运动后血流。但是，一个阶段 3评估DMD长期他达拉非治疗的临床试验未能使步行6分钟的步行受益测试（主要结果），尽管有改善的手臂功能。基于初级缺乏疗效结果，达拉非被视为DMD治疗。我们假设该账户未能说明对于可变的卧床下降率（可能影响主要结果）和他达拉非参与（需要充分利用腿部肌肉）解释了其缺乏功效。我们的随机，安慰剂控制的探索性临床试验将解决这些限制并寻求他达拉非与结构化运动相结合的概念证明将改善肌肉 DMD中的病理生理和功能。我们的初步数据表明，达拉非可以挽救活动 - DMD男孩（7-12岁）的依赖性血流缺陷。我们的方法是第一个屏幕用于药物反应性（增加肌肉氧合）后。那些反应灵敏的意志被随机分配为达拉非或安慰剂的6个月干预，结构化循环运动训练（以确保定期激活肌肉）。我们将量化对干预的影响血管障碍和肌肉病理生理学（炎症，脂肪积累，线粒体功能障碍），劳累疲劳和循环性能。我们的发现预计将提供1）分层DMD患者最有可能受益于他达拉非作为辅助治疗的标准，2）在DMD中表现出强大的协同作用和运动训练之间的协同作用。它与此R21 FOA将提供初步数据，以培养使用的长期临床试验血管扩张药物和运动训练，有和没有基因替代疗法，将导致DMD治疗的临床意义改善。