Mid-Term Report Summary - CARDIO-IPS (Induced Pluripotent stem Cells: A Novel Strategy to Study Inherited Cardiac Disorders)
The study of several cardiac genetic disorders is hampered by the lack of suitable in vitro human models. The overarching hypothesis of the current project is that the generation of patient-specific human induced pluripotent stem cells (hiPSCs) can allow the development of disease-specific in vitro models; yielding new pathophysiologic insights into several genetic disorders and offering a unique platform to test novel therapeutic strategies. To this end we established patient/disease specific hiPSCs by reprogramming skin fibroblasts derived from patients with different arrhythmogenic syndromes (disorders that may lead to sudden death in otherwise healthy individuals) such as different types of the long QT syndrome and catecholaminergic polymorphic ventricular tachycardia as well as from patients with different cardiomyopathies (heart muscle disorders) such as hypertrophic cardiomyopathy, Pompe glycogen storage disease, and arrhythmogenic right ventricular cardiomyopathy (ARVC). The different hiPSCs lines generated were then coaxed to differentiate into the cardiac lineage, where bonefide human heart cells were generated. Detailed molecular, structural, functional, and pharmacological studies were then performed in some of these patient-specific hiPSCs-derived cardiomyocytes (hiPSCs-CMs) to characterize their phenotypic properties, with specific emphasis on their ultrastructural, electrophysiological, and calcium handling properties. These studies demonstrated the ability of the hiPSCs-CMs to recapitulate the clinical disease process also in the culture dish and to provide novel insights into disease pathogenesis. The development of such hiPSCs models represents a potential paradigm shift in the way we study genetic disorders and could lead to better understanding of such diseases, to the development of novel therapies, and to the ability to individualize patient-specific therapies in the future.