Genome Editing of Human iPSCs to Study Inherited Hypertrophic Cardiomyopathy

Stanford University, Stanford CA

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Abstract

? DESCRIPTION (provided by applicant): Familial hypertrophic cardiomyopathy (HCM) is an inheritable autosomal dominant trait, displaying abnormal thickening of myocardium and histologic manifestations. To date, considerable studies have uncovered the correlation between gene mutations and HCM. However, the underlying developmental etiology remains largely unknown due to the limited access to obtain cardiomyocytes (CMs) from patients with this disease. Recent breakthrough in generation of human induced pluripotent stem cells (iPSCs) from skin or blood and de novo differentiation into cardiomyocytes (iPSC-CMs) offers a novel source for disease modeling. Using this strategy, we have a unique opportunity to study the developmental etiology of HCM. This proposal will demonstrate the feasibility of elucidating myofilament diseases with patient-specific iPSC-CMs and genome-edited iPSC-CMs. Aim 1 is to generate iPSCs from patients with HCM mutations and matched family controls as well as unrelated healthy donors. Aim 2 is to determine the extent of disease by performing molecular and functional analyses of iPSC-CMs. Aim 3 is to recapitulate sarcomeric HCM disease phenotype with genome editing technology. In summary, we believe findings from this study will yield novel insights into our understanding of the developmental etiology of HCM and give rise to potential new targets for therapeutic strategy of HCM.