Understanding and Improving Therapies for the Muscular Dystrophies through Noninvasive Biomarkers

项目概要/摘要 项目3作为该中心申请的转化项目，补充临床前 项目1和2的治疗开发。基于我们在非侵入性磁共振成像领域的专业知识， 共振（MR）生物标志物的发展，我们将检查患者的代谢重塑 杜氏肌营养不良症（DMD）治疗的新兴疗法和最常见的 肢带型肌营养不良症，LGMDR 1（也称为LGMD 2A）。有效的临床 管理这两种形式的肌营养不良症可能需要多种伴随 治疗策略，这可能会产生积极或消极的代谢后果。 我们的中心假设是营养不良肌肉的疾病进展与 代谢重塑，这可以通过不同的药理学策略来调节， 为治疗开发提供新的生物标志物。肥胖和增加 代谢危险因素已被认为是DMD的标志性特征， 长期使用糖皮质激素类固醇（GC）。微肌营养不良蛋白（µDys）基因治疗已经出现 作为一种有前途的治疗策略，肌营养不良蛋白的显著恢复， 在早期临床试验中获得了有利的临床数据。然而，由于 预计µDys蛋白、nNOS定位受损和/或钙处理异常 基因治疗后持续存在（项目1的重点）。此外，免疫反应管理 需要伴随长期使用GC。为了进一步了解µDys基因的作用， 在DMD患者的治疗中，目标1将检查肌肉代谢的MR生物标志物， 在用AAV-µDys治疗的DMD患者中，病程将 以多块肌肉为特征，并与未经治疗的年龄 匹配的DMD（历史数据）和贝克尔肌营养不良症患者;后一种患者是 预期会反映基因治疗后的表型特征。在目标2中， 广泛的自然史数据/生物样本，并获得正在进行的临床研究，以检查 不同GC给药方案（与项目2协同）和长期GC暴露对 DMD的肌肉和全身代谢。最后，在目标3中，我们将扩展 生物标志物对LGMDR 1起作用，LGMDR 1是治疗开发中服务不足的患者群体。我们 将使用MR生物标志物和代谢组学的组合来表征 疾病进展，并帮助确定治疗目标和新的生物标志物，为未来的临床 审判

Project Summary/Abstract Project 3 serves as the translational project for this Center application, complementing preclinical therapeutic development in Projects 1 & 2. Building on our expertise in noninvasive magnetic resonance (MR) biomarker development, we will examine metabolic remodeling in patients with Duchenne muscular dystrophy (DMD) treated with emerging therapies and the most common form of limb girdle muscular dystrophy, LGMDR1 (also referred to as LGMD2A). Effective clinical management in both forms of muscular dystrophy will likely require multiple concomitant treatment strategies, which can have positive or negative metabolic consequences. Our central hypothesis is that disease progression in dystrophic muscle is associated with metabolic remodeling, which can be modulated by different pharmacologic strategies and exploited to provide novel biomarkers for therapeutic development. Obesity and an increase in metabolic risk factors have been recognized as hallmark features of DMD, exacerbated by chronic use of glucocorticoid steroids (GC). Micro-dystrophin (µDys) gene therapy has emerged as a promising treatment strategy, with significant restoration of dystrophin protein and favorable clinical data in early stage clinical trials. However, due to the truncated nature of the µDys protein, impaired nNOS localization and/or aberrant calcium handling are expected to persist post gene therapy (Focus of Project 1). In addition, immune response management requires concomitant chronic use of GC. To gain further insight into the effects of µDys gene therapy in individuals with DMD, Aim 1 will examine MR biomarkers of muscle metabolism, inflammation, and composition in DMD patients treated with AAV-µDys. The disease course will be characterized in multiple muscles and compared with the disease trajectory in untreated, age matched DMD (historical data) and Becker muscular dystrophy patients; the latter patients are expected to mirror the phenotypic profile post-gene therapy. In Aim 2, we will leverage extensive natural history data/biosamples and access to ongoing clinical studies to examine the effect of different GC dosing regimens (Synergy with Project 2) and chronic GC exposure on both muscle and whole-body metabolism in DMD. Finally, in Aim 3, we will extend our biomarker work to LGMDR1, an underserved patient population in therapeutic development. We will use a combination of MR biomarkers and metabolomics to characterize the natural history of disease progression and help identify therapeutic targets and novel biomarkers for future clinical trials.