Kaufmann Walter E, Luu Skylar, Budimirovic Dejan B
Boston Children's Hospital, Boston, MA, 02115, USA.
Emory University School of Medicine, Atlanta, GA, 30322, USA.
Curr Neurol Neurosci Rep. 2024 Dec 6;25(1):7. doi: 10.1007/s11910-024-01394-3.
Preclinical and clinical evidence support the notion that neurodevelopmental disorders (NDDs) are synaptic disorders, characterized by excitatory-inhibitory imbalance. Despite this, NDD drug development programs targeting glutamate or gamma-aminobutyric acid (GABA) receptors have been largely unsuccessful. Nonetheless, recent drug trials in Rett syndrome (RTT), fragile X syndrome (FXS), and other NDDs targeting other mechanisms have met their endpoints. The purpose of this review is to identify the basis of these successful studies.
Despite increasing evidence of disruption in synaptic homeostasis, most genetic variants associated with NDDs implicate proteins involved in cell regulation and not in neurotransmission. Metabolic processes, in particular mitochondrial function, appear to play a role in NDD pathophysiology. NDDs are also characterized by distinctive cell signaling abnormalities, which link cellular and synaptic homeostasis. Recent successful trials in NDDs, including those of trofinetide, the first drug specifically approved for one of these disorders (i.e., RTT), implicate the targeting of downstream processes (i.e., signaling pathways) rather than neurotransmitter receptors. Recent positive drug studies in NDDs and their underlying mechanisms, in conjunction with new knowledge on the pathophysiology of these disorders, support the concept that targeting signaling and cellular and synaptic homeostasis may be a preferred approach for ameliorating synaptic abnormalities in many NDDs.
临床前和临床证据支持神经发育障碍（NDDs）是突触障碍这一观点，其特征为兴奋 - 抑制失衡。尽管如此，针对谷氨酸或γ - 氨基丁酸（GABA）受体的NDD药物研发项目大多未取得成功。然而，最近针对雷特综合征（RTT）、脆性X综合征（FXS）和其他NDDs的靶向其他机制的药物试验达到了终点。本综述的目的是确定这些成功研究的基础。
尽管有越来越多的证据表明突触稳态受到破坏，但与NDDs相关的大多数基因变异涉及参与细胞调节而非神经传递的蛋白质。代谢过程，特别是线粒体功能，似乎在NDD病理生理学中起作用。NDDs还具有独特的细胞信号异常特征，这些异常将细胞和突触稳态联系起来。最近在NDDs中的成功试验，包括曲非尼肽（第一种专门获批用于其中一种疾病，即RTT的药物）的试验，表明靶向下游过程（即信号通路）而非神经递质受体。最近在NDDs中的阳性药物研究及其潜在机制，连同对这些疾病病理生理学的新知识，支持了这样一种概念，即靶向信号转导以及细胞和突触稳态可能是改善许多NDDs中突触异常的首选方法。
