Department of Pediatrics, School of Medicine, Fukuoka University, Fukuoka, Japan; Research Institute for the Molecular Pathomechanisms of Epilepsy, Fukuoka University, Fukuoka, Japan.
Research Institute for the Molecular Pathomechanisms of Epilepsy, Fukuoka University, Fukuoka, Japan.
Mol Cell Neurosci. 2020 Oct;108:103535. doi: 10.1016/j.mcn.2020.103535. Epub 2020 Aug 4.
Epilepsy is among the most common neurological disorders, affecting approximately 50 million people worldwide. Importantly, epilepsy is genetically and etiologically heterogenous, but several epilepsy types exhibit similar clinical presentations. Epilepsy-associated genes are being identified. However, the molecular pathomechanisms remain largely unknown. Approximately one-third of epilepsy is refractory to multiple conventional anti-epileptic drugs (AEDs). Induced pluripotent stem cells (iPSCs) provide an excellent tool to study the pathomechanisms underlying epilepsy and to develop novel treatments. Indeed, disease-specific iPSCs have been established for several genetic epilepsies. In particular, the molecular mechanisms underlying certain developmental and epileptic encephalopathies, such as Dravet syndrome, have been revealed. Modeling epilepsy with iPSCs enables new drug development based on the elucidated pathomechanisms. This can also be used to evaluate conventional AEDs and drug repurposing. Furthermore, transplanting neuronal cells derived from iPSCs into the brain has great potential to treat refractory epilepsies. Recent advances in iPSC technology have enabled the generation of neuronal organoids, or "mini brains." These organoids demonstrate electrophysiological activities similar to those of the brain and have the potential for extensive epilepsy research opportunities. Thus, the application of iPSCs in epilepsy provides insight into novel treatments based on the molecular pathomechanisms of epilepsy. In this review, we comprehensively discuss the studies conducted on iPSCs established for genetic epilepsy or epilepsies without major structural dysmorphic features.
癫痫是最常见的神经障碍之一，影响全球约 5000 万人。重要的是，癫痫在遗传和病因上具有异质性，但几种癫痫类型表现出相似的临床特征。目前正在鉴定与癫痫相关的基因。然而，分子病理机制在很大程度上仍不清楚。大约三分之一的癫痫对多种传统抗癫痫药物（AEDs）耐药。诱导多能干细胞（iPSCs）为研究癫痫的病理机制和开发新的治疗方法提供了极好的工具。事实上，已经为几种遗传性癫痫建立了疾病特异性 iPSCs。特别是，已经揭示了某些发育性和癫痫性脑病（如 Dravet 综合征）背后的分子机制。使用 iPSCs 模拟癫痫可以基于阐明的病理机制进行新药开发。这也可用于评估传统 AEDs 和药物再利用。此外，将源自 iPSCs 的神经元细胞移植到大脑中具有治疗耐药性癫痫的巨大潜力。iPSC 技术的最新进展使得神经元类器官或“迷你大脑”的产生成为可能。这些类器官表现出类似于大脑的电生理活动，并且具有广泛的癫痫研究机会。因此，iPSCs 在癫痫中的应用为基于癫痫的分子病理机制的新型治疗方法提供了深入了解。在这篇综述中，我们全面讨论了针对遗传性癫痫或无主要结构畸形特征的癫痫建立的 iPSCs 进行的研究。
