Human Induced Pluripotent Stem Cell (hiPSC)-Derived Cells to Assess Drug Cardiotoxicity: Opportunities and Problems

Abstract

Billions of US dollars are invested every year by the pharmaceutical industry in drug development, with the aim of introducing new drugs that are effective and have minimal side effects. Thirty percent of in-pipeline drugs are excluded in an early phase of preclinical and clinical screening owing to cardiovascular safety concerns, and several lead molecules that pass the early safety screening make it to market but are later withdrawn owing to severe cardiac side effects. Although the current drug safety screening methodologies can identify some cardiotoxic drug candidates, they cannot accurately represent the human heart in many aspects, including genomics, transcriptomics, and patient- or population-specific cardiotoxicity. Despite some limitations, human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are a powerful and evolving technology that has been shown to recapitulate many attributes of human cardiomyocytes and their drug responses. In this review, we discuss the potential impact of the inclusion of the hiPSC-CM platform in premarket candidate drug screening.

Keywords: cardiac; cardiomyocyte; cardiotoxicity; chemotherapy; differentiation; human induced pluripotent stem cells; pharmacogenomics.

Figure 1

(a) On-market drugs and cardiovascular adverse events. Data adapted from the SIDER 4.1: Side Effect Resource (http://sideeffects.embl.de) database of drugs and adverse drug reactions (3). (b) Drug withdrawal due to serious cardiovascular adverse reactions. Sixty-three drugs in different therapeutic classes were withdrawn from the market between 1953 and 2013 owing to serious cardiotoxic effects.

Figure 2

Six major phenotypic areas that can be assessed in human induced pluripotent stem cell–derived cardiomyocytes (hiPSC-CMs) and high-throughput methods that can be applied. Other abbreviations: ECR, extracellular acidification rate; OCR, oxygen consumption rate.

Figure 3

Application of human induced pluripotent stem cell–derived cardiomyocytes (hiPSC-CMs) in the drug discovery pipeline and possible modalities by which hiPSC-CMs can be used during drug discovery.