Project 3 - Walter_Vandenborne

Abstract: Project 3 Project 3 serves as the clinical research 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 determine the contemporary natural history of gene therapy treated patients with Duchenne muscular dystrophy (DMD) and in a rare form of limb girdle muscular dystrophy, sarcoglycanopathy (LGMDR3/R5). Our central hypothesis is that quantitative MR can be used as a biomarker for early skeletal and cardiac muscle disease progression and inflammation, to monitor the impact of AAV based therapies. Micro-dystrophin (µDys) gene therapy has emerged as a promising treatment strategy with recent FDA approval changing the landscape in DMD. However, the truncated nature of the µDys protein and the need for high concentrations of current AAVs may limit therapeutic efficacy and present some unique challenges. Therefore, in Aim 1 we will determine the disease trajectory of individuals with DMD treated with a clinically approved µDys-AAV and evaluate the impact on cardiac muscle. In Aim 2, we will extend our biomarker work to LGMDR3/R5, an underserved patient population in therapeutic development. We will use a combination of MR biomarkers and serum/urine biomarkers to characterize the natural history of disease progression and help identify therapeutic targets and novel biomarkers for future AAV clinical trials in this population. Finally, in Aim 3, we will validate MR parametric mapping of the myocardium to detect cardiac remodeling, inflammation, and any reaction to a large dose of AAV in a large rodent model of DMD, with the goal of implementing this approach in young children undergoing gene therapy.