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Modeling Drug‐Induced Neuropathy Using Human iPSCs for Predictive Toxicology
Author(s) -
Ohara R,
Imamura K,
Morii F,
Egawa N,
Tsukita K,
Enami T,
Shibukawa R,
Mizuno T,
Nakagawa M,
Inoue H
Publication year - 2017
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1002/cpt.562
Subject(s) - induced pluripotent stem cell , neurotoxicity , pharmacology , drug , neurite , toxicity , medicine , drug development , biology , neuroscience , in vitro , biochemistry , embryonic stem cell , gene
Drugs under development can cause unpredicted toxicity in humans due to differential drug responsiveness between humans and other disease models, resulting in clinical trial failures. Human induced pluripotent stem cells (iPSCs) are expected to represent a useful tool for toxicity testing. However, among many assays, appropriate cellular assays for predicting neurotoxicity in an iPSC‐based model are still uncertain. Here we generated neurons from iPSCs of Charcot–Marie–Tooth disease (CMT) patients. Some CMT patients are sensitive to anticancer drugs and present with an adverse reaction of neuropathy. We analyzed cellular phenotypes and found that mitochondria in neurites of CMT neurons were morphologically shorter and showed slower mobility compared to control. A neurosphere assay showed that treatment with drugs known to cause neuropathy caused mitochondrial aggregations in neurites with adenosine triphosphate shortage in both CMT and control neurons, although more severely in CMT. These findings suggest that the genetically susceptible model could provide a useful tool to predict drug‐induced neurotoxicity.