Neurodevelopmental disorders (NDD) encompass a range of conditions marked by abnormal brain development in conjunction with impaired cognitive, emotional and behavioural functions. Transgenic animal models, mainly rodents, traditionally served as key tools for deciphering the molecular mechanisms driving NDD physiopathology and significantly contributed to the development of pharmacological interventions aimed at treating these disorders. However, the efficacy of these treatments in humans has proven to be limited, due in part to the intrinsic constraint of animal models to recapitulate the complex development and structure of the human brain but also to the phenotypic heterogeneity found between affected individuals. Significant advancements in the field of induced pluripotent stem cells (iPSCs) offer a promising avenue for overcoming these challenges. Indeed, the development of advanced differentiation protocols for generating iPSC-derived brain organoids gives an unprecedented opportunity to explore human neurodevelopment. This review provides an overview of how 3D brain organoids have been used to investigate various NDD (i.e. Fragile X syndrome, Rett syndrome, Angelman syndrome, microlissencephaly, Prader-Willi syndrome, Timothy syndrome, tuberous sclerosis syndrome) and elucidate their pathophysiology. We also discuss the benefits and limitations of employing such innovative 3D models compared to animal models and 2D cell culture systems in the realm of personalized medicine.

中文翻译：

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使用脑类器官破译神经发育障碍的生理病理学


神经发育障碍 （NDD） 包括一系列以大脑发育异常以及认知、情绪和行为功能受损为特征的病症。转基因动物模型，主要是啮齿动物，传统上是破译驱动 NDD 生理病理学的分子机制的关键工具，并为旨在治疗这些疾病的药物干预的发展做出了重大贡献。然而，这些治疗在人类中的疗效已被证明是有限的，部分原因是动物模型在概括人脑的复杂发育和结构方面的内在限制，但也由于受影响个体之间发现的表型异质性。诱导多能干细胞 （iPSC） 领域的重大进展为克服这些挑战提供了一条有希望的途径。事实上，用于生成 iPSC 衍生的脑类器官的高级分化方案的开发为探索人类神经发育提供了前所未有的机会。本综述概述了如何使用 3D 脑类器官研究各种 NDD（即脆性 X 综合征、Rett 综合征、Angelman 综合征、小脑畸形、Prader-Willi 综合征、Timothy 综合征、结节性硬化症综合征）并阐明其病理生理学。我们还讨论了在个性化医疗领域与动物模型和 2D 细胞培养系统相比，采用这种创新 3D 模型的优势和局限性。