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

Kiyoshi Takasuna; Keiichi Asakura; Seiichi Araki; Hiroyuki Ando; Katsuyuki Kazusa; Takashi Kitaguchi; Takeshi Kunimatsu; Shinobu Suzuki; Norimasa Miyamoto

doi:10.1016/j.vascn.2016.09.004

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

J Pharmacol Toxicol Methods. 2017 Jan-Feb:83:42-54. doi: 10.1016/j.vascn.2016.09.004. Epub 2016 Sep 17.

Authors

Kiyoshi Takasuna¹, Keiichi Asakura², Seiichi Araki³, Hiroyuki Ando⁴, Katsuyuki Kazusa⁵, Takashi Kitaguchi⁶, Takeshi Kunimatsu⁷, Shinobu Suzuki⁸, Norimasa Miyamoto⁹

Affiliations

¹ Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan; Japan Pharmaceutical Manufacturers Association Drug Evaluation Committee, Non-Clinical Evaluation Expert Committee, TF2, Japan; Consortium for Safety Assessment using Human iPS Cells (CSAHi): HEART team, Japan. Electronic address: takasuna.kiyoshi.a3@daiichisankyo.co.jp.
² Japan Pharmaceutical Manufacturers Association Drug Evaluation Committee, Non-Clinical Evaluation Expert Committee, TF2, Japan; Consortium for Safety Assessment using Human iPS Cells (CSAHi): HEART team, Japan; Discovery Research Labs., Nippon Shinyaku Co., Ltd., Kyoto, Japan.
³ Japan Pharmaceutical Manufacturers Association Drug Evaluation Committee, Non-Clinical Evaluation Expert Committee, TF2, Japan; Consortium for Safety Assessment using Human iPS Cells (CSAHi): HEART team, Japan; Safety Research Department, ASKA Pharmaceutical Co., Ltd., Kanagawa, Japan.
⁴ Japan Pharmaceutical Manufacturers Association Drug Evaluation Committee, Non-Clinical Evaluation Expert Committee, TF2, Japan; Consortium for Safety Assessment using Human iPS Cells (CSAHi): HEART team, Japan; Safety Research Laboratories, Ono Pharmaceutical Co., Ltd., Fukui, Japan.
⁵ Japan Pharmaceutical Manufacturers Association Drug Evaluation Committee, Non-Clinical Evaluation Expert Committee, TF2, Japan; Consortium for Safety Assessment using Human iPS Cells (CSAHi): HEART team, Japan; Drug Safety Research Laboratories, Astellas Pharma Inc., Osaka, Japan.
⁶ Japan Pharmaceutical Manufacturers Association Drug Evaluation Committee, Non-Clinical Evaluation Expert Committee, TF2, Japan; Consortium for Safety Assessment using Human iPS Cells (CSAHi): HEART team, Japan; Discovery Research, Mochida Pharmaceutical Co., Ltd., Shizuoka, Japan.
⁷ Japan Pharmaceutical Manufacturers Association Drug Evaluation Committee, Non-Clinical Evaluation Expert Committee, TF2, Japan; Consortium for Safety Assessment using Human iPS Cells (CSAHi): HEART team, Japan; Preclinical Research Laboratories, Sumitomo Dainippon Pharma Co., Ltd., Osaka, Japan.
⁸ Japan Pharmaceutical Manufacturers Association Drug Evaluation Committee, Non-Clinical Evaluation Expert Committee, TF2, Japan; Consortium for Safety Assessment using Human iPS Cells (CSAHi): HEART team, Japan; Pharmacokinetics and Non-Clinical Safety Dept., Nippon Boehringer Ingelheim Co., Ltd., Hyogo, Japan.
⁹ Japan Pharmaceutical Manufacturers Association Drug Evaluation Committee, Non-Clinical Evaluation Expert Committee, TF2, Japan; Consortium for Safety Assessment using Human iPS Cells (CSAHi): HEART team, Japan; Biopharmaceutical Assessments Core Function Unit Medicine Development Center Eisai Co., Ltd., Eisai Co., Ltd., Ibaraki, Japan.

PMID: 27646297
DOI: 10.1016/j.vascn.2016.09.004

Abstract

Recent increasing evidence suggests that the currently-used platforms in vitro I_Kr 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.

Keywords: CSAHi; Ca transient; Cardiac liability; Human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs); Impedance; Motion field imaging; Multi-electrode arrays; Multi-parametric; Simulation; Stem cell.

Publication types

Review

MeSH terms

Action Potentials / drug effects*
Arrhythmias, Cardiac / chemically induced*
Cardiotoxicity
Cell Culture Techniques
Cells, Cultured
Dose-Response Relationship, Drug
Drug-Related Side Effects and Adverse Reactions*
Humans
Induced Pluripotent Stem Cells / drug effects*
Induced Pluripotent Stem Cells / physiology
Microelectrodes
Models, Cardiovascular*
Myocytes, Cardiac / drug effects*
Myocytes, Cardiac / physiology
Pharmaceutical Preparations / administration & dosage

Substances

Pharmaceutical Preparations