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

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

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.

MeSH terms

  • CRISPR-Cas Systems / genetics
  • Cell Death / drug effects
  • Gene Editing
  • Gene Expression Profiling*
  • Genome, Human
  • Heart Ventricles / drug effects
  • Heart Ventricles / metabolism
  • Humans
  • Induced Pluripotent Stem Cells / cytology*
  • Induced Pluripotent Stem Cells / metabolism*
  • Inverted Repeat Sequences / genetics
  • Myocytes, Cardiac / cytology*
  • Myocytes, Cardiac / metabolism
  • Rosiglitazone
  • Tacrolimus / adverse effects*
  • Thiazolidinediones / adverse effects*
  • Treatment Outcome

Substances

  • Thiazolidinediones
  • Rosiglitazone
  • Tacrolimus