Comprehensive in vitro cardiac safety assessment using human stem cell technology: Overview of CSAHi HEART initiative

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• 作者：Kiyoshi Takasuna^a ; ^b ; ^c ; ^{takasuna.kiyoshi.a3@daiichisankyo.co.jp} ; Keiichi Asakura^b ; ^c ; ^d ; Seiichi Araki^b ; ^c ; ^e ; Hiroyuki Ando^b ; ^c ; ^f ; Katsuyuki Kazusa^b ; ^c ; ^g ; Takashi Kitaguchi^b ; ^c ; ^h ; Takeshi Kunimatsu^b ; ^c ; ⁱ ; Shinobu Suzuki^b ; ^c ; ^j ; Norimasa Miyamoto^b ; ^c ; ^k
• 关键词：CSAHi ; Consortium for Safety Assessment using Human iPS Cells ; FPDc10 ; concentration inducing FPDc prolongation by 10% ; CMIS ; cell motion imaging system ; hiPS-CMs ; human induced pluripotent stem cell-derived cardiomyocytes ; CRD ; contraction-relaxation duration ; IBD10 ; impedance-based duration from 10% rising to 10% falling amplitude ; PWD90 ; peak width duration at 90% amplitude ; MEA ; multi-electrode array ; CPMP ; committee for proprietary medicinal products ; APD ; action potential duration ; TdP ; To
• 刊名：Journal of Pharmacological and Toxicological Methods
• 出版年：2017
• 出版时间：January-February 2017
• 年：2017
• 卷：83
• 期：Complete
• 页码：42-54
• 全文大小：1956 K
• 卷排序：83

文摘

Recent increasing evidence suggests that the currently-used platforms in vitro IKr and APD, and/or in vivo QT assays are not fully predictive for TdP, and do not address potential arrhythmia (VT and/or VF) induced by diverse mechanisms of action. In addition, other cardiac safety liabilities such as functional dysfunction of excitation-contraction coupling (contractility) and structural damage (morphological damage to cardiomyocytes) are also major causes of drug attrition, but current in vitro assays do not cover all these liabilities.We organized the Consortium for Safety Assessment using Human iPS cells (CSAHi; http://csahi.org/en/), based on the Japan Pharmaceutical Manufacturers Association (JPMA), to verify the application of human iPS/ES cell-derived cardiomyocytes in drug safety evaluation. The main goal of the CSAHi HEART team has been to propose comprehensive screening strategies to predict a diverse range of cardiotoxicities by using recently introduced platforms (multi-electrode array (MEA), patch clamp, cellular impedance, motion field imaging [MFI], and Ca transient systems) while identifying the strengths and weaknesses of each.Our study shows that hiPS-CMs used in these platforms have pharmacological responses more relevant to humans in comparison with existent hERG, APD or Langendorff (MAPD/contraction) assays, and not only MEA but also other methods such as impedance, MFI, and Ca transient systems would offer paradigm changes of platforms for predicting drug-induced QT risk and/or arrhythmia or contractile dysfunctions. Furthermore, we propose a potential multi-parametric platform in which field potential (MEA)-Ca transient-contraction (MFI) could be evaluated simultaneously as an ideal novel platform for predicting a diversity of cardiac toxicities, namely whole effects on the excitation-contraction cascade.