Gene Therapy Strategies to Treat Heart Failure in Duchenne Muscular Dystrophy


Pre-Clinical Research

Poster Number: 238


Asuka Eguchi, PhD, Stanford University, Adriana Gonzalez, Stanford University, Sofía Torres-Bigio, Stanford University, Sriram Bhimaraju, Stanford University, Gaspard Pardon, PhD, École Polytechnique Fédérale de Lausanne, Foster Birnbaum, Stanford University, Beth Pruitt, PhD, University of California, Santa Barbara, Helen Blau, PhD, Stanford University

Duchenne muscular dystrophy (DMD) is a severe muscle wasting disease caused by the lack of dystrophin. Dilated cardiomyopathy is the leading cause of death in DMD patients. Smaller versions of dystrophin, amenable to packaging into adeno-associated virus (AAV), have shown to be effective in improving skeletal muscle function; however, the functional benefit of these transgenes in delaying heart failure is unknown. Moreover, recent deaths in AAV-mediated gene therapy underscores the urgency toward developing safer gene delivery methods. To establish more effective gene therapy strategies, we are identifying design principles for the treatment of neuromuscular disorders. To address DMD heart dysfunction, specifically, we compare the functional efficacy of the three dystrophin variants currently in clinical trials. We differentiate patient-derived induced pluripotent stem cells (iPSCs) to cardiomyocytes to model disease phenotypes. Previously, we reported that mechanical contraction and calcium handling are impaired in DMD iPSC-cardiomyocytes. To test the functional benefit of the transgenes, we performed traction force microscopy, which provides multiparametric measurements of contraction, and calcium imaging with a ratiometric calcium-binding dye. Our results show a partial rescue of contractile deficits and aberrant calcium handling, emphasizing the need for new design variants that address cardiomyocyte dysfunction.