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.

中文翻译：

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神经元类器官模型在药物发现中的新兴作用：潜在的应用和实施障碍

临床管线中药物的高失败率可能部分是由于临床前模型不足，尤其是针对神经系统疾病和神经退行性疾病的模型所致。此类临床前动物模型通常会遭受基本物种差异的困扰，很少能概括神经系统疾病的所有方面，而常规的二维（2D）体外模型无法捕获大脑组织的三维空间组织和细胞间相互作用据推测对中枢神经系统的功能至关重要。最近的研究表明，干细胞衍生的神经元类器官比2D神经元培养物更具生理相关性，因为它们的细胞结构，电生理特性，人类起源和基因表达。因此，有兴趣将这种生理相关模型纳入化合物筛选和药物发现中的前导优化工作中。但是，尽管它们具有相关性，但与以前使用的临床前模型相比，对其预测价值知之甚少。实际上，由于低通量和乏味的生成方案，固有的可变性以及缺乏兼容的中高通量筛选分析方法，一些人一直在谨慎地广泛采用类器官技术来进行药物发现。因此，微流体平台，专门的生物反应器和自动测定法已经并且正在开发以解决这些缺陷。