TY - JOUR
T1 - Unlocking personalized biomedicine and drug discovery with human induced pluripotent stem cell-derived cardiomyocytes
T2 - Fit for purpose or forever elusive?
AU - De Korte, Tessa
AU - Katili, Puspita A.
AU - Mohd Yusof, Nurul A.N.
AU - Van Meer, Berend J.
AU - Saleem, Umber
AU - Burton, Francis L.
AU - Smith, Godfrey L.
AU - Clements, Peter
AU - Mummery, Christine L.
AU - Eschenhagen, Thomas
AU - Hansen, Arne
AU - Denning, Chris
N1 - Funding Information:
The authors are supported by the National Centre for the Replacement, Refinement & Reduction of Animals in Research (grants CRACK IT:35911-259146 and NC/K000225/1); the British Heart Foundation (grants SP/15/9/31605, RG/15/6/31436, PG/14/59/31000, RG/14/1/30588, and P47352/CRM); the German Research Foundation (DFG-Es-88/12-1, HA3423/5-1); the European Research Council (ERC-AG-IndivuHeart and ERC-AdG STEMCARDIOVASC); the European Commission (FP7-Biodesign); the German Centre for Cardiovascular Research (DZHK) and the German Ministry of Education and Research; Freie und Hansestadt Hamburg; ZonMW (ZorgOnderzoek Nederland—Medische wetenschappen); and MKMD (Meer Kennis met Minder Dieren) Applications of Innovations 2015 to 2016.
Publisher Copyright:
Copyright © 2020 by Annual Reviews. All rights reserved.
PY - 2020/1/6
Y1 - 2020/1/6
N2 - In recent decades, drug development costs have increased by approximately a hundredfold, and yet about 1 in 7 licensed drugs are withdrawn from the market, often due to cardiotoxicity. This review considers whether technologies using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) could complement existing assays to improve discovery and safety while reducing socioeconomic costs and assisting with regulatory guidelines on cardiac safety assessments. We draw on lessons from our own work to suggest a panel of 12 drugs that will be useful in testing the suitability of hiPSC-CM platforms to evaluate contractility. We review issues, including maturity versus complexity, consistency, quality, and cost, while considering a potential need to incorporate auxiliary approaches to compensate for limitations in hiPSC-CM technology. We give examples on how coupling hiPSC-CM technologies with Cas9/CRISPR genome engineering is starting to be used to personalize diagnosis, stratify risk, provide mechanistic insights, and identify new pathogenic variants for cardiovascular disease.
AB - In recent decades, drug development costs have increased by approximately a hundredfold, and yet about 1 in 7 licensed drugs are withdrawn from the market, often due to cardiotoxicity. This review considers whether technologies using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) could complement existing assays to improve discovery and safety while reducing socioeconomic costs and assisting with regulatory guidelines on cardiac safety assessments. We draw on lessons from our own work to suggest a panel of 12 drugs that will be useful in testing the suitability of hiPSC-CM platforms to evaluate contractility. We review issues, including maturity versus complexity, consistency, quality, and cost, while considering a potential need to incorporate auxiliary approaches to compensate for limitations in hiPSC-CM technology. We give examples on how coupling hiPSC-CM technologies with Cas9/CRISPR genome engineering is starting to be used to personalize diagnosis, stratify risk, provide mechanistic insights, and identify new pathogenic variants for cardiovascular disease.
KW - cardiac safety
KW - cardiomyocyte contraction
KW - Cas9/CRISPR
KW - CiPA
KW - human induced pluripotent stem cell-derived cardiomyocytes
KW - organ-on-a-chip
UR - http://www.scopus.com/inward/record.url?scp=85077034178&partnerID=8YFLogxK
U2 - 10.1146/annurev-pharmtox-010919-023309
DO - 10.1146/annurev-pharmtox-010919-023309
M3 - Review article
C2 - 31506008
AN - SCOPUS:85077034178
VL - 60
SP - 529
EP - 551
JO - Annual Review of Pharmacology and Toxicology
JF - Annual Review of Pharmacology and Toxicology
SN - 0362-1642
ER -
