ヒトiPS細胞由来神経細胞を用いた創薬における神経毒性研究

抄録

In small molecule drug discovery, evaluating both on-target and off-target toxicities at early stages is critical to preventing dropout in later phases. When dealing with neurotoxicity, determining the safety margin and risk-to-benefit ratio is pivotal for go/no-go decisions in drug projects. When a safety margin is inadequate, the mechanism of neurotoxicity should be elucidated to potentially avoid it. Here, we present an evaluation method using human iPSC-derived neurons and describe its application in a project at Chugai Pharmaceutical. In that project, we observed neurotoxicity in a preliminary canine toxicity study at the expected human effective exposure level. Given the low likelihood of on-target toxicity based on the target safety assessment, we focused on off-target possibilities. We began by using an in vitro functional assay to identify a suspicious target: monoamine transporter (MAT) inhibition. Subsequent in vitro experiments used a microelectrode array (MEA) with iPSC-derived neurons to investigate whether MAT inhibition mediates neurotoxicity. The principal component analysis of MEA indicated that the neurotoxic compound had a profile similar to known MAT inhibitors, suggesting that MAT inhibition may have caused the neurotoxicity. Conversely, in our in vivo approach examining the effects of metabolites, we did not find a correlation with neurotoxicity. In this presentation, I will share our integrated approach to avoiding compound-mediated neurotoxicity and to elucidating neurotoxic mechanisms using human iPSC-derived neurons. The limitations of in vitro nonclinical safety studies will also be discussed.