Departments of Pediatrics, Pharmacology, Neurology, and Otolaryngology, University of Colorado, School of Medicine and Children's Hospital Colorado, United States.
Departments of Pediatrics and Neurology, University of Colorado School of Medicine and Children's Hospital Colorado, United States.
Neuropharmacology. 2021 Nov 1;199:108805. doi: 10.1016/j.neuropharm.2021.108805. Epub 2021 Sep 22.
Considerable genetic variation of N-methyl-d-aspartate receptors (NMDARs) has recently become apparent, with many hundreds of de novo variants identified through widely available clinical genetic testing. Individuals with GRIN variants present with neurological conditions such as epilepsy, autism, intellectual disability (ID), movement disorders, schizophrenia and behavioral disorders. Determination of the functional consequence of genetic variation for NMDARs should lead to precision therapeutics. Furthermore, genetic animal models harboring human variants have the potential to reveal mechanisms that are shared among different neurological conditions, providing strategies that may allow treatment of individuals who are refractory to therapy. Preclinical studies in animal models and small open label trials in humans support this idea. However, additional functional data for variants and animal models corresponding to multiple individuals with the same genotype are needed to validate this approach and to lead to thoughtfully designed, randomized, placebo-controlled clinical trials, which could provide data in order to determine safety and efficacy of potential precision therapeutics.
最近，N-甲基-D-天冬氨酸受体 (NMDAR) 的遗传变异已经变得非常明显，通过广泛可用的临床基因测试，已经鉴定出数百种新的变体。具有 GRIN 变体的个体表现出神经疾病，如癫痫、自闭症、智力障碍 (ID)、运动障碍、精神分裂症和行为障碍。确定 NMDAR 遗传变异的功能后果应导致精准治疗。此外，携带人类变体的遗传动物模型有可能揭示不同神经疾病之间共享的机制，为那些对治疗有抗药性的个体提供治疗策略。动物模型的临床前研究和人类的小型开放标签试验支持这一观点。然而，需要更多具有相同基因型的多个个体的变体和动物模型的功能数据来验证这种方法，并进行精心设计的、随机的、安慰剂对照的临床试验，这些临床试验可以提供数据，以确定潜在精准治疗的安全性和有效性。
