Abstract
Over the years, numerous groups have employed human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) as a superb human-compatible model for investigating the function and dysfunction of cardiomyocytes, drug screening and toxicity, disease modeling and for the development of novel drugs for heart diseases. In this review, we discuss the broad use of iPSC-CMs for drug development and disease modeling, in two related themes. In the first theme—drug development, adverse drug reactions, mechanisms of cardiotoxicity and the need for efficient drug screening protocols—we discuss the critical need to screen old and new drugs, the process of drug development, marketing and Adverse Drug reactions (ADRs), drug-induced cardiotoxicity, safety screening during drug development, drug development and patient-specific effect and different mechanisms of ADRs. In the second theme—using iPSC-CMs for disease modeling and developing novel drugs for heart diseases—we discuss the rationale for using iPSC-CMs and modeling acquired and inherited heart diseases with iPSC-CMs.
Highlights
One of the major hurdles during the tremendously expensive and extensive process of drug development is the discovery of Adverse Drug reactions (ADRs) which may interrupt prematurely the agonizing journey of bringing a new chemical entity (NCE) to the market
Despite the widespread use of induced pluripotent stem cells (iPSCs)-CMs for different purposes, soon after their introduction, it became clear that iPSC-CMs generated by different differentiation protocols exhibit diverse immaturity/maturity status compared to adult cardiomyocytes, and, the urgent need to generate mature-like cardiomyocytes has emerged
Application of thapsigargin onto forskolin-treated CPVT1 iPSC-CMs reduced afterdepolarization events post-pacing, implying the role of Ca2+ stores in DADs development. These results demonstrated the ability of CPVT1 iPSC-CMs to recapitulate the disease phenotype, the contribution of β-adrenergic signaling to increased propensity to arrhythmogenic events and the potential of using CPVT1 iPSC-CMs for specific drug-screening and evaluating suitable drugs
Summary
One of the major hurdles during the tremendously expensive and extensive process of drug development is the discovery of Adverse Drug reactions (ADRs) which may interrupt prematurely the agonizing journey of bringing a new chemical entity (NCE) to the market. ADRs including cardiotoxicity can be discovered during the long drug development phase or, worse, after the drug was released to the market (i.e., post-marketing) This may cause a catastrophic clinical outcome to the patients, as well as a considerable economic burden to the insurance and healthcare systems. We focus on the process of drug development and address in depth the issues of ADRs, drug-induced cardiotoxicity, safety screening during drug development and different mechanisms underlying ADRs. The second part is focused on the use of human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) for disease modeling and drug discovery. As indicated by the US Food and Drugs Administration (Food and Drug Administration (2004) Challenge and opportunity on the critical path to new medical products.): “The inability to better assess and predict product safety leads to failures during clinical development and, occasionally, after marketing” [3]
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