Development of an evaluation assay for drug-induced seizure liability using human iPSC derived neurons

Abstract

Human induced pluripotent stem cell-derived neurons are promising for use in toxicity evaluations in nonclinical studies. One of the major adverse events affecting the central nervous system observed during clinical trials is convulsions. Micro-electrode array (MEA) systems have recently attracted attention for use in evaluating the convulsion potential of a drug because they non-invasively measure the electrophysiological activity of neural networks at multiple sites in a high-throughput manner. Over twelve compounds including convulsants were tested at 5 concentrations. Using principal component analysis, clustering analysis, and artificial intelligence (AI), we have succeeded in separating the responses between convulsive drugs and negative control, and in classifying the mechanism of actions of drugs from spontaneous firing data. The MEA assay using hiPSC-derived neurons and our analysis method will be effective for predicting the seizure liability and mechanism of action of new drugs.