Towards Precision Medicine with Human Induced Pluripotent Stem Cells for Dystrophin Associated Cardiomyopathy.

With the increasing age of patients with Duchenne muscular dystrophy, progressive muscle degeneration is also accompanied by cardiomyopathy, which can have a fatal outcome in the most serious patients. Cardiomyopathy is linked to the absence, or insufficiency, of cardiac dystrophin (dystrophin-associated cardiomyopathy, DAC). At the cellular level it causes mechanical damage, dysregulation of metabolic pathways and inflammatory processes, death of the cardiomyocyte with adipofibrose replacement; at the organ level it manifests itself with dysfunctions especially affecting the left ventricle, arrhythmias, dilated cardiomyopathy and heart failure. ACD is variable between patients, however genotypic characterization studies of the mutation in the dystrophin gene have not yet contributed to elucidating the mechanisms underlying the heterogeneity of cardiomyopathy and the available information is insufficient to predict the risk of ACD. This knowledge gap affects clinical decision making, e.g. as regards the timing for the initiation of cardiac pharmacotherapy, to date without specific therapy and often delayed until signs of ACD are evident. Hence, the need to correlate clinical data with specific data derived from DAC models that are accurate and prognostic is very relevant. In this project, the researchers will organize in a systematic way the collection of clinical cardiological data of subjects with Duchenne or Becker dystrophy who manifest DAC, biological samples and iPS cells derived from the same patients to define a personalized diagnostic-therapeutic approach.