Comparisons of Microdystrophin Gene Therapy for Duchenne Muscular Dystrophy


Pre-Clinical Research

Poster Number: S19


Asuka Eguchi, PhD, University of California, Irvine, Adriana Fernanda Gonzalez, Stanford University, Sriram Bhimaraju, Stanford University, Abhishree Mishra, Stanford University, Sofía Torres-Bigio, 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 in animal models; however, the functional benefit of these transgenes in the DMD heart remains to be explored. To determine the efficacy of microdystrophin gene therapy, we compare three microdystrophin variants in DMD cardiomyocytes differentiated from human induced pluripotent stem cells (iPSCs). DMD iPSC-cardiomyocytes exhibit morphological deficits, aberrant calcium handling, and poor mechanical contraction. To test the functional benefit of the transgenes, we performed calcium imaging with a ratiometric calcium-binding dye and traction force microscopy, which provides multiparametric measurements of contraction. Our results show a partial rescue of disease phenotypes, suggesting that the design of a new dystrophin variant may be necessary for therapeutic efficacy in DMD cardiomyocytes.