Department of Pediatrics/Rady Children's Hospital, Department of Cellular & Molecular Medicine, School of Medicine, University of California San Diego, La Jolla, CA, USA.
Department of Neurosciences, School of Medicine, University of California San Diego, La Jolla, CA, USA.
EMBO Mol Med. 2021 Jan 11;13(1):e12523. doi: 10.15252/emmm.202012523. Epub 2020 Dec 8.
Duplication or deficiency of the X-linked MECP2 gene reliably produces profound neurodevelopmental impairment. MECP2 mutations are almost universally responsible for Rett syndrome (RTT), and particular mutations and cellular mosaicism of MECP2 may underlie the spectrum of RTT symptomatic severity. No clinically approved treatments for RTT are currently available, but human pluripotent stem cell technology offers a platform to identify neuropathology and test candidate therapeutics. Using a strategic series of increasingly complex human stem cell-derived technologies, including human neurons, MECP2-mosaic neurospheres to model RTT female brain mosaicism, and cortical organoids, we identified synaptic dysregulation downstream from knockout of MECP2 and screened select pharmacological compounds for their ability to treat this dysfunction. Two lead compounds, Nefiracetam and PHA 543613, specifically reversed MECP2-knockout cytologic neuropathology. The capacity of these compounds to reverse neuropathologic phenotypes and networks in human models supports clinical studies for neurodevelopmental disorders in which MeCP2 deficiency is the predominant etiology.
X 连锁的 MECP2 基因的重复或缺失可靠地导致严重的神经发育障碍。MECP2 突变几乎普遍负责雷特综合征（RTT），并且 MECP2 的特定突变和细胞嵌合体可能是 RTT 症状严重程度谱的基础。目前尚无针对 RTT 的临床批准的治疗方法，但人类多能干细胞技术为识别神经病理学和测试候选治疗方法提供了一个平台。我们使用一系列越来越复杂的人类干细胞衍生技术，包括人类神经元、模拟 RTT 女性大脑嵌合体的 MECP2 嵌合神经球，以及皮质类器官，鉴定了 MECP2 敲除后的突触失调，并筛选了一些药物化合物，以测试它们治疗这种功能障碍的能力。两种先导化合物，奈非那韦和 PHA 543613，特异性地逆转了 MECP2 敲除的细胞学神经病理学。这些化合物在人类模型中逆转神经病理表型和网络的能力支持针对以 MeCP2 缺乏为主要病因的神经发育障碍的临床研究。
