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.

Public Health Relevance

Familial hypertrophic cardiomyopathy (HCM) is the most commonly inherited cardiovascular disease, affecting 1 in 500 people worldwide with outcomes ranging from reduced quality of life to sudden cardiac death (SCD). Although surgical reduction of hypertrophic heart (e.g., myomectomy) can improve clinical symptoms and implantable defibrillator can prevent SCD, no specific pharmacological therapy is currently available to cure HCM. To date, the majority of HCM studies have been performed in cell lines and animal models. Due to physiological differences between animals and humans, as well as the secondary abnormalities resulting from end-stage HCM, these studies provided only limited understanding of the underlying mechanism of HCM disease phenotype. Using a multi-disciplinary approach, we will provide novel mechanistic insights into the pathological processes of sarcomeric HCM by deriving patient-specific iPSCs and genome-edited iPSCs to recapitulate the disease process and understand its mechanism of progression.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
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Special Emphasis Panel (ZRG1-CB-J (55))
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Desvigne-Nickens, Patrice
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Stanford University
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