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 肌营养不良症 (DMD) 是一种无法治愈的神经肌肉疾病，其特征是肌肉快速退化、线粒体和血管损伤，导致过早丧失的步行和死亡率。新兴的疾病缓解疗法旨在部分恢复缺失的肌膜蛋白抗肌营养不良蛋白的水平（对于稳定和分子水平至关重要信号）。尽管它们有望改善患有以下疾病的男孩的肌肉功能和日常活动 DMD，大多数并非旨在纠正血管损伤（因为它们不能恢复 nNO 运动期间和运动后促进血管舒张所需的信号传导）。因此，活跃的肌肉接受这些疗法治疗的 DMD 男孩将出现灌注不足，导致损伤和尽管部分肌营养不良蛋白替代，仍感到疲劳。他达拉非是 FDA 批准的血管扩张药物填补这一治疗空白的潜力；临床前和临床数据表明它可以改善灌注、疲劳患有 DMD 的小鼠的运动和损伤，以及患有 DMD 的男孩的运动后血流。然而，一个阶段 3 项评估长期他达拉非治疗 DMD 的临床试验未能使 6 分钟步行受益尽管手臂功能有所改善，但测试（主要结果）。基于初级阶段缺乏疗效结果，他达拉非作为 DMD 治疗药物已被驳回。我们假设未能考虑到用于不同速率的动态下降（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）是其缺乏功效的原因。我们的随机、安慰剂对照的探索性临床试验将解决这些局限性并寻求概念证明他达拉非结合结构化运动可以改善肌肉 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动- 患有 DMD 的男孩（7-12 岁）存在依赖性血流缺陷。我们的方法是首先筛选一剂后的药物反应（肌肉氧合增加）。那些有反应的人会随机接受为期 6 个月的他达拉非或安慰剂干预，并结合结构化周期运动训练（以确保定期激活肌肉）。我们将量化干预措施的影响血管损伤和肌肉病理生理学（炎症、脂肪堆积、线粒体功能障碍）、劳力疲劳和骑行表现。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受益的 DMD 患者进行分层的标准和 2) 证明药物对 DMD 的影响和运动训练之间存在强大的协同作用。它与 R21 FOA，因为它将提供初步数据，以促进使用 R21 FOA 进行稳健、长期的临床试验血管扩张药物和运动训练，无论有或没有基因替代疗法，导致 DMD 治疗有临床意义的改善。