Abstract Body: Introduction: Duchenne muscular dystrophy is a severe muscle wasting disease caused by the lack of dystrophin expression. Dilated cardiomyopathy is the leading cause of death in DMD patients. Delivery of full-length dystrophin is not practical due to the large size of the gene; however, smaller variants of dystrophin, called microdystrophins, have shown promise in restoring function to the skeletal muscle. These microdystrophins are currently being administered to patients in clinical trials; however, therapeutic efficacy in the DMD heart is unknown due to challenges in modeling heart failure in animal models.

Hypothesis: We hypothesized that microdystrophin gene therapy can ameliorate disease phenotypes in DMD cardiomyocytes differentiated from human induced pluripotent stem cells (iPSCs).

Methods: This study uses human iPSCs to model the functional deficits of DMD cardiomyocytes. We delivered microdystrophins and a variant twice the size of microdystrophin to DMD iPSC-cardiomyocytes. We performed ratiometric calcium imaging to evaluate calcium handling and longitudinal cell viability assays to assess cell survival.

Results: We found that DMD iPSC-cardiomyocytes exhibit hallmarks of disease, including aberrant calcium handling and poor viability. Our results show that microdystrophins modestly rescue disease phenotypes but do not fully address the cellular deficits exhibited by DMD cardiomyocytes.

Conclusions: These findings emphasize a need for new gene therapy strategies for the treatment of heart failure in DMD.