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 language | English (US) |
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Pages (from-to) | 311-325 |
Number of pages | 15 |
Journal | Cell stem cell |
Volume | 19 |
Issue number | 3 |
DOIs | |
State | Published - 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