Understanding and Improving Therapies for the Muscular Dystrophies through Noninvasive Biomarkers

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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.