The successful derivation of human induced pluripotent stem cells (hiPSCs) from somatic cells offers significant potential to overcome obstacles in the field of cardiovascular disease. hiPSC-derived cardiac cells can now provide incredible potential for disease modeling in vitro and regenerative medicine therapies in vivo. Recently, several exciting demonstrations of the disease modeling capability of hiPSC- derived cardiac cells have been published (e.g., Timothy syndrome, LEOPARD syndrome). These patient-specific hiPSC-CMs have been found to recapitulate the disease phenotypes. In contrast to Timothy and LEOPARD syndrome (which are considered orphan diseases), familial dilated cardiomyopathy (DCM) is the most common cause of heart failure and hence places a tremendous burden on the healthcare system in the US and worldwide. Here we seek to derive hiPSCs from patients with familial dilated cardiomyopathy (Aim 1), determine the phenotype of hiPSC-cardiac cells from DCM patients versus healthy controls (Aim 2), and evaluate their functionality after genetic rescue using homologous recombination (Aim 3). We believe the findings here should have broad clinical and scientific impact toward better understanding on the molecular and cellular basis of DCM.

Public Health Relevance

Familial dilated cardiomyopathy (DCM) is the most common cause of heart failure and places a tremendous burden on the healthcare system in the US and worldwide. From the early beginnings of the genomic era and since the description of the first familial DCM causing mutations, investigators have attempted to study its mechanistic basis by correlating genotype with clinical phenotype expression. Unfortunately, these studies have been severely hampered by the inaccessibility of human cardiomyocytes. In this grant proposal, we will generate human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) from patients with DCM. We will perform detailed and mechanistic analyses to determine the functional and molecular phenotypes of DCM. This approach will dramatically enhance our ability to perform future high-throughput drug screening, evaluate gene and cell therapies, and assess potential novel therapies of DCM.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Myocardial Ischemia and Metabolism Study Section (MIM)
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Buxton, Denis B
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Stanford University
Internal Medicine/Medicine
Schools of Medicine
United States
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Ma, Ning; Zhang, Joe Z; Itzhaki, Ilanit et al. (2018) Determining the Pathogenicity of a Genomic Variant of Uncertain Significance Using CRISPR/Cas9 and Human-Induced Pluripotent Stem Cells. Circulation 138:2666-2681
Nishiga, Masataka; Guo, Hongchao; Wu, Joseph C (2018) Induced pluripotent stem cells as a biopharmaceutical factory for extracellular vesicles. Eur Heart J 39:1848-1850
Garg, Priyanka; Oikonomopoulos, Angelos; Chen, Haodong et al. (2018) Genome Editing of Induced Pluripotent Stem Cells to Decipher Cardiac Channelopathy Variant. J Am Coll Cardiol 72:62-75
Rhee, June-Wha; Wu, Joseph C (2018) Cardiac Cell Cycle Activation as a Strategy to Improve iPSC-Derived Cardiomyocyte Therapy. Circ Res 122:14-16
Garg, Priyanka; Garg, Vivek; Shrestha, Rajani et al. (2018) Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes as Models for Cardiac Channelopathies: A Primer for Non-Electrophysiologists. Circ Res 123:224-243
Lee, Andrew S; Inayathullah, Mohammed; Lijkwan, Maarten A et al. (2018) Prolonged survival of transplanted stem cells after ischaemic injury via the slow release of pro-survival peptides from a collagen matrix. Nat Biomed Eng 2:104-113
Zhao, Xin; Chen, Haodong; Xiao, Dan et al. (2018) Comparison of Non-human Primate versus Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes for Treatment of Myocardial Infarction. Stem Cell Reports 10:422-435
Oikonomopoulos, Angelos; Kitani, Tomoya; Wu, Joseph C (2018) Pluripotent Stem Cell-Derived Cardiomyocytes as a Platform for Cell Therapy Applications: Progress and Hurdles for Clinical Translation. Mol Ther 26:1624-1634
Lee, Jaecheol; Shao, Ning-Yi; Paik, David T et al. (2018) SETD7 Drives Cardiac Lineage Commitment through Stage-Specific Transcriptional Activation. Cell Stem Cell 22:428-444.e5
Knowles, Joshua W; Ashley, Euan A (2018) Cardiovascular disease: The rise of the genetic risk score. PLoS Med 15:e1002546

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