ヒトiPS/ES 由来心筋細胞を用いた心機能毒性評価系への期待

抄録

Since the Committee for Proprietary Medicinal Products (CPMP) of the European Union issued in 1997 a “points to consider” document for the assessment of the potential for QT interval prolongation by non-cardiovascular agents to predict drug-induced torsades de pointes (TdP), the QT liability has become the critical safety issue in the development of pharmaceuticals. As TdP is usually linked to delayed cardiac repolarization, international guideline (ICH S7B) has advocated the standard repolarization assays such as in vitro I_Kr (hERG current) and in vivo QT interval, or in vitro APD (as a follow up) as the best biomarkers for predicting the TdP risk. However, the recent increasing evidence suggests that the currently used above biomarkers and/or assays are not fully predictive for TdP, and also does not address potential arrhythmia (VT and/or VF) induced by other mechanisms including the selective disruption of hERG protein trafficking, the interaction with other ion channels, pumps, exchangers, or transporters, and dysfunction of exciting-contraction coupling and cellular damage. There is, therefore, an urgent need for other surrogate markers or assays that can predict a wide range of cardiac toxicity potential of drug candidates. A recent advance in technology for large-scale production of human stem cell derived cardiomyocytes (hiPS/hESCM) has encouraged us to develop the new platform over traditional cell and ex vivo animal models for cardiac safety assessment. Indeed, the combination with modified analytical techniques such as multi-electrode array, patch clamp, impedance, motion vector, or optical imaging and hiPS/hES-CM offer new comprehensive pre-clinical human models capable of predicting a wide range of cardiac liability and their mechanisms. The platforms will open novel opportunities for a reliable, cost- and time-effective, and translational research in human cardiac toxicity during early development phase.