A novel in vitro Duchenne Muscular Dystrophy cardiomyopathy model: human iPSC-derived cardiomyocytes for mechanistic studies

Duchenne muscular dystrophy (DMD) is a wasting disease of striated muscle resulting from membrane fragility. Life expectancy of DMD patients is significantly prolonged thanks to improved standards of care that target the respiratory and cardiac functions as well as motor rehabilitation. DMD-related cardiomyopathy remains, however, an important aspect to study in order to find specific therapeutic options. All previous studies on this disease have been conducted on animal models and novel therapies cannot be easily translated to humans. With this project we aim to obtain an in vitro model of DMD cardiomyopathy, employing human pluripotent stem cells (hiPSCs) differentiated into cardiomyocytes (hiPSC-CMs). Mature cells derived from the urine of DMD patients will be reprogrammed to become “pluripotent”, meaning they have the potential to give rise to other cell types, including cardiac cells. These hiPSC-CMs cells will be grown on peculiar custom-made surfaces in long-term cultures to improve their maturation and will be compared with analogous cells from healthy donors to identify the cellular and molecular determinants of cardiac dysfunction in DMD-cardiomyopathy. Specifically we will study how the contractile and the electrical properties of these cells are impaired over time to identify specific molecular abnormalities that may represent novel targets for therapy. We believe that this assay represents a promising model to study the cellular pathophysiology of DMD cardiomyopathy. By studying multiple cell lines from different DMD patients, this project will set the stage for patient-specific genotype-driven clinical management and therapy.