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Evaluating the use of microelectrode array technology and cell-based neuronal culture models for proconvulsant risk assessment: progress from the HESI NeuTox Consortium
Citation:
Millard, D., A. Nicolini, C. Arrowood, J. Bradley, C. Strock, T. Freudenrich, K. Wallace, Tim Shafer, M. Cato, L. Saavedra, D. Haag, T. Feaster, B. Anson, G. Luerman, D. Hess, Y. Shi, J. Li, H. Shi, P. Levesque, M. Kreir, H. Lu, I. Suzuke, A. Odawara, Y. Kanda, D. Herr, R. Roberts, AND J. Pierson. Evaluating the use of microelectrode array technology and cell-based neuronal culture models for proconvulsant risk assessment: progress from the HESI NeuTox Consortium. Safety Pharmacology Society, Washi, District Of Columbia, September 30 - October 03, 2018.
Impact/Purpose:
This is a HESI sponsored, multi-laboratory project that is evaluating the use of neuronal networks grown on microelectrode arrays (MEAs) for early pre-clinical identification of compounds that may cause seizures in humans. The goal is to identify patterns of activity in in vitro neural networks that are indicative of seizures in vivo. Such an approach will be useful for identification of chemicals that may cause seizures in humans as part of evaluation of chemicals for health effects under the Lautenberg Chemical Safety Act
Description:
The occurrence of drug-induced seizures is an important liability in drug discovery and development that can result in attrition for candidate drugs or withdrawal from the market. Thus, the pharmaceutical industry is motivated to detect proconvulsant risk early in the drug discovery and development process for CNS and non-CNS targets. Current approaches for evaluating proconvulsant risk, such as seizure threshold assays or EEG monitoring, rely on rodent animal models, which can be expensive and are often limited to later stages in drug development. Emerging methods utilizing in vitro cell-based assays of functional neurophysiology have shown promise in identifying neuro-active agents and may demonstrate value for proconvulsant risk assessment earlier in drug discovery. Furthermore, such approaches may also be useful for identification of chemicals with proconvulsant actions under the Lautenberg Chemical Safety Act and determination of doses in the first-in-human clinical trials. Specifically, the electrophysiological activity of networked neuronal cultures can be measured and quantified using multiwell microelectrode array (MEA) instrumentation. However, these studies are characterized by a lack of consensus on cell models, experimental conditions, analytical techniques, and assay endpoints. Here, we describe the recent progress for a consortium of stakeholders aiming to improve and standardize proconvulsant risk assessment using in vitro methods. The NeuTox consortium, organized by the Health and Environmental Science Institute (HESI), comprises representatives from the pharmaceutical industry, cell and laboratory instrumentation providers, contract research organizations, and academic researchers. Broadly, the NeuTox mission is to characterize the reliability and accuracy of detecting drug-induced seizurogenic activity using MEA technology and neuronal cultures. Towards this end, the group has reviewed retrospective data, developed a standardized assay protocol, selected a 12 compound training set, and coordinated an international multi-site pilot study. The results of the pilot study provide for comparisons across various rodent and human induced pluripotent stem (iPS) cell-derived neural models and evaluate the ability of quantitative measures of functional neural network activity to discriminate between proconvulsant and control compounds within the training set. This abstract does not represent US EPA policy.