Assessment of a 3D neural spheroid model to detect pharmaceutical-induced neurotoxicity

Main Article Content

Qin Wang
Jennifer D. Cohen
Tomoya Yukawa
Heather Estrella
Chris Leonard
Jairo Nunes
Colin Choi
Lauren Lewis
Kevin S. Baker
Kazuhiro Kuga
Yvonne P. Dragan
Matthew P. Wagoner
Nibha Mishra

Abstract

Drug-induced neurotoxicity is a leading cause of safety-related attrition for therapeutics in clinical trials, often driven by poor predictive capability of preclinical in vitro and in vivo models of neurotoxicity. Over a dozen different iPSC-derived 3D spheroids have been published in recent years, but their ability to predict neurotoxicity in patients has not been evaluated, nor compared with the predictive power of nonclinical species. To assess the predictive capabilities of the human iPSC-derived neural spheroids (microBrains), we used 84 structurally diverse pharmaceuticals with robust clinical and preclinical datasets with varying degrees of seizurogenic and neurodegenerative liability. Drug-induced changes in neural viability and phenotypic calcium bursts were assessed using 7 endpoints based on calcium oscillation profiles and cellular ATP levels. These endpoints normalized by therapeutic exposure were used to build logistic regression models to establish endpoint cutoffs and evaluate probability for clinical neurotoxicity. The neurotoxicity score calculated from the logistic regression model could distinguish neurotoxic from non-neurotoxic clinical molecules with a specificity as high as 93.33% and a sensitivity of 53.49%, demonstrating a very low false positive rate for the prediction of seizures, convulsions and neurodegeneration. In contrast, nonclinical species showed a higher sensitivity (75%) and much lower specificity (30.4%). The neural spheroids demonstrated higher likelihood ratio positive and inverse likelihood ratio negative compared with nonclinical safety studies. This assay has the potential to be used as a predictive assay to detect neurotoxicity in early drug discovery, aiding in the early identification of compounds that eventually may fail due to neurotoxicity.

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How to Cite
Wang, Q., Cohen, J. D., Yukawa, T., Estrella, H., Leonard, C., Nunes, J. ., Choi, C., Lewis, L. ., Baker, K. S., Kuga, K., Dragan, Y. P., Wagoner, M. P. and Mishra, N. (2022) “Assessment of a 3D neural spheroid model to detect pharmaceutical-induced neurotoxicity”, ALTEX - Alternatives to animal experimentation. doi: 10.14573/altex.2112221.
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