Approach to Neurotoxicity using Human iPSC Neurons: Consortium for Safety Assessment using Human iPS Cells

Abstract

Neurotoxicity, as well as cardiotoxicity and hepatotoxicity, resulting from administration of a test article is considered a major adverse effect both pre-clinically and clinically. Among the different types of neurotoxicity occurring during the drug development process, seizure is one of the most serious one. Seizure occurrence is usually assessed using in vivo animal models, the Functional Observational Battery, the Irwin test or electroencephalograms. In in vitro studies, a number of assessments can be performed using animal organs/cells. Interestingly, recent developments in stem cell biology, especially the development of Human-Induced Pluripotent Stem (iPS) cells, are enabling the assessment of neurotoxicity in human iPS cell-derived neurons. Further, a Multi-Electrode Array (MEA) using rodent neurons is a useful tool for identifying seizure-inducing compounds. The Consortium for Safety Assessment using Human iPS Cells (CSAHi; http://csahi.org/en/) was established in 2013 by the Japan Pharmaceutical Manufacturers Association (JPMA) to verify the application of human iPS cell-derived neuronal cells to drug safety evaluation. The Neuro Team of CSAHi has been attempting to evaluate the seizure risk of compounds using the MEA platform. Here, we review the current status of neurotoxicity and recent work, including problems related to the use of the MEA assay with human iPS neuronal cell-derived neurons, and future developments.