title: Transcriptome Profiling of Patient-Specific Human iPSC-Cardiomyocytes Predicts Individual Drug Safety and Efficacy Responses In Vitro.
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.
authors.affiliation: 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.
authors.forename: Elena
authors.initials: E
authors.lastname: Matsa
authors.affiliation: 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.
authors.forename: Paul W
authors.initials: PW
authors.lastname: Burridge
authors.affiliation: 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.
authors.forename: Kun-Hsing
authors.initials: KH
authors.lastname: Yu
authors.affiliation: Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: John H
authors.initials: JH
authors.lastname: Ahrens
authors.affiliation: 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.
authors.forename: Vittavat
authors.initials: V
authors.lastname: Termglinchan
authors.affiliation: 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.
authors.forename: Haodi
authors.initials: H
authors.lastname: Wu
authors.affiliation: 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.
authors.forename: Chun
authors.initials: C
authors.lastname: Liu
authors.affiliation: 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.
authors.forename: Praveen
authors.initials: P
authors.lastname: Shukla
authors.affiliation: 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.
authors.forename: Nazish
authors.initials: N
authors.lastname: Sayed
authors.affiliation: 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.
authors.forename: Jared M
authors.initials: JM
authors.lastname: Churko
authors.affiliation: 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.
authors.forename: Ningyi
authors.initials: N
authors.lastname: Shao
authors.affiliation: Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Nicole A
authors.initials: NA
authors.lastname: Woo
authors.affiliation: Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Alexander S
authors.initials: AS
authors.lastname: Chao
authors.affiliation: Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Gold
authors.affiliation: 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.
authors.forename: Ioannis
authors.initials: I
authors.lastname: Karakikes
authors.affiliation: Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Snyder
authors.affiliation: 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.
authors.forename: Joseph C
authors.initials: JC
authors.lastname: Wu
mesh_terms: D064113:CRISPR-Cas Systems / Q000235:genetics; D016923:Cell Death / Q000187:drug effects; D000072669:Gene Editing; D020869:Gene Expression Profiling; D015894:Genome, Human; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology* / Q000378:metabolism*; D055029:Inverted Repeat Sequences / Q000235:genetics; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000378:metabolism; D000077154:Rosiglitazone; D016559:Tacrolimus / Q000009:adverse effects*; D045162:Thiazolidinediones / Q000009:adverse effects*; D016896:Treatment Outcome
chemical_list: D045162:Thiazolidinediones; D000077154:Rosiglitazone; D016559:Tacrolimus
keywords: cardiomyocytes; induced pluripotent stem cells; personalized drug safety and efficacy; precision medicine