Recapitulation of Clinical Individual Susceptibility to Drug-Induced QT Prolongation in Healthy Subjects Using IPSC-Derived Cardiomyocytes

Overview

Journal Stem Cell Reports

Publisher Cell Press

Specialty Cell Biology

Date 2017 Jan 24

PMID 28111276

Citations 26

Authors

Tadahiro Shinozawa

Koki Nakamura

Masanobu Shoji

Maya Morita

Maya Kimura

Hatsue Furukawa

Hiroki Ueda

Masanari Shiramoto

Kyoko Matsuguma

Yoshikazu Kaji

Ippei Ikushima

Makoto Yono

Shyh-Yuh Liou

Hirofumi Nagai

Atsushi Nakanishi

Keiji Yamamoto

Seigo Izumo

Affiliations

Soon will be listed here.

Abstract

To predict drug-induced serious adverse events (SAE) in clinical trials, a model using a panel of cells derived from human induced pluripotent stem cells (hiPSCs) of individuals with different susceptibilities could facilitate major advancements in translational research in terms of safety and pharmaco-economics. However, it is unclear whether hiPSC-derived cells can recapitulate interindividual differences in drug-induced SAE susceptibility in populations not having genetic disorders such as healthy subjects. Here, we evaluated individual differences in SAE susceptibility based on an in vitro model using hiPSC-derived cardiomyocytes (hiPSC-CMs) as a pilot study. hiPSCs were generated from blood samples of ten healthy volunteers with different susceptibilities to moxifloxacin (Mox)-induced QT prolongation. Different Mox-induced field potential duration (FPD) prolongation values were observed in the hiPSC-CMs from each individual. Interestingly, the QT interval was significantly positively correlated with FPD at clinically relevant concentrations (r > 0.66) in multiple analyses including concentration-QT analysis. Genomic analysis showed no interindividual significant differences in known target-binding sites for Mox and other drugs such as the hERG channel subunit, and baseline QT ranges were normal. The results suggest that hiPSC-CMs from healthy subjects recapitulate susceptibility to Mox-induced QT prolongation and provide proof of concept for in vitro preclinical trials.

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