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Cell Stem Cell. 2016 Sep 1;19(3):311-25. doi: 10.1016/j.stem.2016.07.006. Epub 2016 Aug 18.

Transcriptome Profiling of Patient-Specific Human iPSC-Cardiomyocytes Predicts Individual Drug Safety and Efficacy Responses In Vitro.

Author information

1
Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA; Departments of Medicine and Radiology, Stanford University School of Medicine, Stanford, CA 94305, USA; Institute of Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address: ematsa@stanford.edu.
2
Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA; Departments of Medicine and Radiology, Stanford University School of Medicine, Stanford, CA 94305, USA; Institute of Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA; Center for Pharmacogenomics, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
3
Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA; Biomedical Informatics Training Program, Stanford University School of Medicine, Stanford, CA 94305, USA.
4
Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
5
Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA; Departments of Medicine and Radiology, Stanford University School of Medicine, Stanford, CA 94305, USA; Institute of Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
6
Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA; Departments of Medicine and Radiology, Stanford University School of Medicine, Stanford, CA 94305, USA.
7
Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA.
8
Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA; Departments of Medicine and Radiology, Stanford University School of Medicine, Stanford, CA 94305, USA; Institute of Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address: joewu@stanford.edu.

Abstract

Understanding individual susceptibility to drug-induced cardiotoxicity is key to improving patient safety and preventing drug attrition. Human induced pluripotent stem cells (hiPSCs) enable the study of pharmacological and toxicological responses in patient-specific cardiomyocytes (CMs) and may serve as preclinical platforms for precision medicine. Transcriptome profiling in hiPSC-CMs from seven individuals lacking known cardiovascular disease-associated mutations and in three isogenic human heart tissue and hiPSC-CM pairs showed greater inter-patient variation than intra-patient variation, verifying that reprogramming and differentiation preserve patient-specific gene expression, particularly in metabolic and stress-response genes. Transcriptome-based toxicology analysis predicted and risk-stratified patient-specific susceptibility to cardiotoxicity, and functional assays in hiPSC-CMs using tacrolimus and rosiglitazone, drugs targeting pathways predicted to produce cardiotoxicity, validated inter-patient differential responses. CRISPR/Cas9-mediated pathway correction prevented drug-induced cardiotoxicity. Our data suggest that hiPSC-CMs can be used in vitro to predict and validate patient-specific drug safety and efficacy, potentially enabling future clinical approaches to precision medicine.

KEYWORDS:

cardiomyocytes; induced pluripotent stem cells; personalized drug safety and efficacy; precision medicine

PMID:
27545504
PMCID:
PMC5087997
DOI:
10.1016/j.stem.2016.07.006
[Indexed for MEDLINE]
Free PMC Article

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