Understanding and Improving Therapies for the Muscular Dystrophies through Noninvasive Biomarkers

项目摘要/摘要 项目3是该中心应用程序的翻译项目，是对临床前应用的补充 项目1和2的治疗进展。以我们在非侵入性磁学方面的专业知识为基础 磁共振(MR)生物标记物的发展，我们将检查患者的代谢重构 杜氏肌营养不良症(DMD)的新兴疗法和最常见的治疗方法 肢带型肌营养不良症，LGMDR1(也称为LGMD2A)。有效的临床应用 这两种形式的肌营养不良症的治疗都可能需要多种伴随因素。 治疗策略，可产生积极或消极的新陈代谢后果。 我们的中心假设是营养不良肌肉的疾病进展与 代谢重塑，可通过不同的药物策略和 被开发来为治疗开发提供新的生物标志物。肥胖症和增加的 代谢危险因素已被认为是DMD的标志特征， 长期使用糖皮质激素(GC)。微肌营养不良蛋白基因治疗应运而生 作为一种有希望的治疗策略，可以显著恢复抗肌营养不良蛋白和 早期临床试验中的有利临床数据。但是，由于 µDys蛋白，受损的nNOS定位和/或异常的钙处理预计会 坚持基因治疗后(项目1的重点)。此外，免疫反应管理 需要伴随着长期使用GC。进一步了解µDys基因的作用 对DMD患者的治疗，AIM 1将检测肌肉代谢的MR生物标记物， AAV-µDys治疗的DMD患者的炎症和成分。病程将会 以多块肌肉为特征，并与未经治疗的年龄、疾病轨迹进行比较 匹配的DMD(历史数据)和Becker肌营养不良患者；后者是 预计将反映基因治疗后的表型特征。在目标2中，我们将利用 广泛的自然历史数据/生物样本和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)和慢性GC暴露对健康的影响 DMD的肌肉代谢和全身代谢均存在。最后，在目标3中，我们将扩展我们的 生物标记物对LGMDR1起作用，LGMDR1是治疗开发中服务不足的患者群体。我们 将使用MR生物标记物和代谢组学的组合来表征 疾病进展并帮助确定治疗靶点和未来临床使用的新生物标记物 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.