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

Elena Matsa*, Paul W. Burridge, Kun Hsing Yu, John H. Ahrens, Vittavat Termglinchan, Haodi Wu, Chun Liu, Praveen Shukla, Nazish Sayed, Jared M. Churko, Ningyi Shao, Nicole A. Woo, Alexander S. Chao, Joseph D. Gold, Ioannis Karakikes, Michael P. Snyder, Joseph C. Wu

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

131 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)311-325
Number of pages15
JournalCell stem cell
Volume19
Issue number3
DOIs
StatePublished - Sep 1 2016

Funding

We acknowledge funding support from NIH grants R01 HL113006, R01 HL123968, R01 HL130020, R01 HL126527, and R01 HL128170 and a Burroughs Wellcome Foundation Innovation in Regulatory Science Award (J.C.W.); the California Institute for Regenerative Medicine Center of Excellence for Stem Cell Genomics grant (GC1R-06673-A) and NIH grant P01 GM099130 (M.P.S.); a National Heart, Lung, and Blood Institute Progenitor Cell Biology Jump Start Award, American Heart Association (AHA) grant 16BGIA27790017, and a Stanford Cardiovascular Institute Seed Grant (E.M.); NIH grant K99 HL121177 and AHA grant 14BGIA20480329 (P.W.B.); a Winston Chen Stanford Graduate Fellowship (K.-H.Y.); and NIH grant K99 HL104002, AHA grant 15BGIA22730027, and Stanford CVI Seed Grant (I.K.).

Keywords

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

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Cell Biology

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