The Emerging Role of Neuronal Organoid Models in Drug Discovery: Potential Applications and Hurdles to Implementation.

Autor:	Struzyna LA; Merck & Co., Inc., Kenilworth, New Jersey., Watt ML; Merck & Co., Inc., Kenilworth, New Jersey Marla.Watt@Merck.com.
Jazyk:	angličtina
Zdroj:	Molecular pharmacology [Mol Pharmacol] 2021 Apr; Vol. 99 (4), pp. 256-265. Date of Electronic Publication: 2021 Feb 05.
DOI:	10.1124/molpharm.120.000142
Abstrakt:	The high failure rate of drugs in the clinical pipeline is likely in part the result of inadequate preclinical models, particularly those for neurologic disorders and neurodegenerative disease. Such preclinical animal models often suffer from fundamental species differences and rarely recapitulate all facets of neurologic conditions, whereas conventional two-dimensional (2D) in vitro models fail to capture the three-dimensional spatial organization and cell-to-cell interactions of brain tissue that are presumed to be critical to the function of the central nervous system. Recent studies have suggested that stem cell-derived neuronal organoids are more physiologically relevant than 2D neuronal cultures because of their cytoarchitecture, electrophysiological properties, human origin, and gene expression. Hence there is interest in incorporating such physiologically relevant models into compound screening and lead optimization efforts within drug discovery. However, despite their perceived relevance, compared with previously used preclinical models, little is known regarding their predictive value. In fact, some have been wary to broadly adopt organoid technology for drug discovery because of the low-throughput and tedious generation protocols, inherent variability, and lack of compatible moderate-to-high-throughput screening assays. Consequently, microfluidic platforms, specialized bioreactors, and automated assays have been and are being developed to address these deficits. This mini review provides an overview of the gaps to broader implementation of neuronal organoids in a drug discovery setting as well as emerging technologies that may better enable their utilization. SIGNIFICANCE STATEMENT: Neuronal organoid models offer the potential for a more physiological system in which to study neurological diseases, and efforts are being made to employ them not only in mechanistic studies but also in profiling/screening purposes within drug discovery. In addition to exploring the utility of neuronal organoid models within this context, efforts in the field aim to standardize such models for consistency and adaptation to screening platforms for throughput evaluation. This review covers potential impact of and hurdles to implementation. Competing Interests: The authors declare there is no conflict of interest. (Copyright © 2021 by The American Society for Pharmacology and Experimental Therapeutics.)
Databáze:	MEDLINE
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