Targeting a Genetic Mutation in Glycine Metabolism with D-Cycloserine

描述（由申请人提供）：我们已经确定了一个复杂的结构重排在9p24.1，隔离与精神病在一个家庭。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，并在突变携带者中是三重的。甘氨酸是N-甲基-D-天冬氨酸受体（NMDAR）的共激动剂。预期GLDC三倍体的携带者具有低水平的脑甘氨酸，导致NMDAR介导的功能减退，其强烈地涉及精神分裂症的病理生理学。基于这种突变的携带者是受益于甘氨酸增强其精神药物治疗方案的强有力候选者的基本原理，我们完成了一项双盲安慰剂对照临床试验，随后是开放标签甘氨酸（6周/组）。在该研究中，与安慰剂相比，甘氨酸组发生了临床显著改善。由于治疗效果所需的甘氨酸剂量（约0.8 g/kg）太高，无法通过胶囊给药，因此甘氨酸必须以粉末（约20 g TID）形式给药，并与食物或液体混合，使其成为长期给药的繁琐化合物。在FDA批准的化合物中，如甘氨酸，也可以使这些个体中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位点的部分激动剂，而且还抑制犬尿烯酸。这两种载体都具有显著升高的犬尿烯酸水平，这可能会增强效果 甘氨酸降解的加速。这项R21申请的目的之一是在该突变携带者中进行双盲安慰剂对照DCS增强试验，并评估急性（8周）和慢性（9个月）DCS增强期间临床症状和神经认知功能的变化。我们还建议进行有针对性的神经生物学随访，以表征这种突变在急性和慢性DCS治疗期间的脑结构，功能和神经化学特性。这些研究将使用质子磁共振光谱探测甘氨酸和谷氨酸体内平衡，并使用诱发反应电位和视网膜神经节细胞反应记录探测NMDA介导的神经传递失调。由于在甘氨酸增强之前和期间进行了类似的研究，因此拟议的研究将提供关于相同个体中两种不同NMDAR调节干预措施效果的补充临床和神经生物学数据。这些结果将显著增强我们对与精神病相关的罕见CNVs的神经生物学及其与疾病病理生理学的相关性的理解。更重要的是，这些结果将继续我们的努力，将病理生理学和医学上可行的治疗干预与潜在的遗传学联系起来，对其他患有神经精神疾病的患者具有潜在的益处，这些患者在相同的基因或其他基因/途径中具有突变，这些突变受到相同或相关异常生物过程的影响。

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.