Targeting a Genetic Mutation in Glycine Metabolism with D-Cycloserine

描述（由申请人提供）：我们在一个家庭中发现了一个复杂的9p24.1结构重排，与精神病分离。重排区域中的一个基因甘氨酸脱羧酶（GLDC）参与神经胶质细胞中甘氨酸的降解，并在突变携带者中复制三倍。甘氨酸是n -甲基- d -天冬氨酸受体（NMDAR）的协同激动剂。GLDC三复制的携带者可能具有低水平的脑甘氨酸，导致nmdar介导的功能减退，这与精神分裂症的病理生理学密切相关。基于这种突变的携带者很有可能从甘氨酸增强其精神药物方案中获益这一基本原理，我们完成了一项双盲安慰剂对照临床试验，随后使用开放标签甘氨酸（6周/组）。在该研究中，与安慰剂相比，甘氨酸有显著的临床改善。由于治疗效果所需的甘氨酸剂量（~0.8 g/kg）太高，不能通过胶囊给药，甘氨酸必须以粉末（~ 20g /kg）的形式给药，并与食物或液体混合，使其成为一种笨重的化合物，难以长期给药。在FDA批准的化合物中，像甘氨酸一样，也可以使这些个体的甘氨酸能张力正常化，d -环丝氨酸（DCS）是最佳选择，因为它不仅是甘氨酸调节部位的部分激动剂，而且还能抑制犬尿酸。两种携带者都有显著升高的犬尿酸水平，这可能会增强这种效果

DESCRIPTION (provided by applicant): We have identified a complex structural rearrangement at 9p24.1 that segregates with psychosis in one family. One gene in the rearranged region, glycine decarboxylase (GLDC), is involved in the degradation of glycine in glia cells and is triplicated in mutation carriers. Glycine is a co-agonist for the N-methyl-D-aspartate receptor (NMDAR). Carriers of the GLDC triplication would be expected to have low levels of brain glycine, resulting in NMDAR-mediated hypofunction, which has been strongly implicated in the pathophysiology of schizophrenia. Based on the rationale that the carriers of this mutation were strong candidates to benefit from glycine augmentation of their psychotropic drug regimens, we completed a double-blind placebo-controlled clinical trial, followed by open-label glycine (six weeks/arm). In that study, clinically significant improvement occurred on glycine compared with placebo. Since the doses of glycine required for a therapeutic effect (~0.8 g/kg) are too high to be administered by capsule, glycine must be administered as a powder (~20 g TID) and mixed with food or liquid, making it a cumbersome compound to deliver on a chronic basis. Of the FDA approved compounds that may, like glycine, also normalize glycinergic tone in these individuals, D-cycloserine (DCS) is the optimal choice since it is not only a partial agonist at the glycine modulatory site, but also inhibits kynurenic acid. Both carriers have significantly elevated levels of kynurenic acid, which may be potentiating the effect of the accelerated degradation of glycine by the triplication. One aim of this R21 application is t carry out a double-blind placebo-controlled DCS augmentation trial in carriers of this mutation and to assess changes in clinical symptoms and neurocognitive function during acute (eight weeks) and chronic (nine months) DCS augmentation. We also propose to carry out targeted neurobiological follow-up in order to characterize the brain structural, functional and neurochemical properties of this mutation during acute and chronic treatment with DCS. These studies will probe glycine and glutamate homeostasis using proton magnetic resonance spectroscopy and dysregulation of NMDA-mediated neurotransmission using evoked response potentials and recordings of responses from retinal ganglion cells. Since similar studies were carried out before and during glycine augmentation, the proposed study will provide complementary clinical and neurobiological data on the effects of two different NMDAR modulatory interventions in the same individuals. The results will significantly enhance our understanding of the neurobiology of rare CNVs associated with psychosis and their relevance to disease pathophysiology. More importantly, the results will continue our efforts to link pathophysiology and a medically actionable treatment intervention to underlying genetics, with potential benefit to other patients with neuropsychiatric disease who have mutations in either the same gene or in other genes/pathways that are impacted by the same or related aberrant biological processes.