Targeting a Genetic Mutation in Glycine Metabolism with D-Cycloserine

用 D-环丝氨酸靶向甘氨酸代谢中的基因突变

• 批准号: 8805873
• 负责人: DEBORAH L LEVY
• 金额: $ 23.38万
• 依托单位: MCLEAN HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-05 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8805873
• 关键词: 9p24.1; Acute; Agonist; Amino Acids; Auditory Evoked Potentials; Autistic Disorder; Biological; Biological Process; Bipolar Disorder; Brain; Cells; Chemistry; Chronic; Cleaved cell; Clinical; Clozaril; Code; Complex; Controlled Clinical Trials; Cycloserine; DNA Sequence Rearrangement; Data; Detection; Diagnosis; Disease; Dose; Double-Blind Method; EP300 gene; Electroretinography; Enzymes; Epilepsy; FDA approved; Family; Food; Functional disorder; Gene Mutation; Genes; Genetic; Genomics; Glutamates; Glycine; Glycine decarboxylase; Homeostasis; Human; Individual; Intellectual functioning disability; Intervention; Kynurenic Acid; Laboratories; Link; Liquid substance; Magnetic Resonance Spectroscopy; Mediating; Metabolism; Mood Disorders; Mothers; Mus; Mutation; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Neurobiology; Neurocognition; Neurocognitive; Neurodevelopmental Disorder; Neuroglia; Pathway interactions; Patients; Pattern; Phenotype; Placebo Control; Placebos; Plasma; Powder dose form; Probability; Property; Protons; Psychiatry; Psychotic Disorders; Psychotropic Drugs; Regimen; Retinal Ganglion Cells; Risk; Schedule; Schizophrenia; Serine; Site; Son; Structure; Symptoms; TNFRSF5 gene; Therapeutic Effect; Translating; Variant; Visual; Vomiting; arm; base; capsule; clinical effect; clinical efficacy; clinical phenotype; clinically significant; drinking; experience; follow-up; gamma-Aminobutyric Acid; mutation carrier; negative mood; neurochemistry; neuropsychiatry; neurotransmission; open label; pill; public health relevance; response; therapeutic target; uptake

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.

描述(申请人提供)：我们在9p24.1处发现了一个复杂的结构重排，在一个家庭中分离出精神病。重组区的一个基因，甘氨酸脱羧酶(GLDC)，参与了胶质细胞中甘氨酸的降解，并且在突变载体中是三倍的。甘氨酸是N-甲基-D-天冬氨酸受体(NMDAR)的共同激动剂。GLDC三倍体携带者的大脑甘氨酸水平可能较低，导致NMDAR介导的功能低下，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是从他们的精神药物方案的甘氨酸增强中受益的强有力的候选者的理论，我们完成了一项双盲安慰剂对照临床试验，随后是开放标记的甘氨酸(6周/臂)。在这项研究中，与安慰剂相比，甘氨酸的临床疗效显著改善。由于治疗效果所需的甘氨酸剂量(~0.8g/kg)太高，不能通过胶囊给药，甘氨酸必须以粉末(~20g TID)的形式给药，并与食物或液体混合，使其成为一种难以长期服用的化合物。在FDA批准的可使这些人的甘氨酸能张力正常化的化合物中，D-环丝氨酸(DC)是最佳选择，因为它不仅是甘氨酸调节部位的部分激动剂，而且还抑制犬尿酸。这两种携带者的犬尿酸水平都显著升高，这可能会增强这种影响 三倍体对甘氨酸的加速降解。R21应用的一个目的是在该突变的携带者中进行一项双盲安慰剂对照的DC增强试验，并评估在急性(8周)和慢性(9个月)DC增强期间临床症状和神经认知功能的变化。我们还建议开展有针对性的神经生物学随访，以表征该突变在急性和慢性使用DC治疗期间的脑结构、功能和神经化学性质。这些研究将使用质子磁共振波谱来探索甘氨酸和谷氨酸的动态平衡，并使用诱发反应电位和视网膜神经节细胞的反应记录来探索NMDA介导的神经传递的失调。由于在甘氨酸增强之前和期间也进行了类似的研究，拟议的研究将提供两种不同的NMDAR调节干预对同一个体的影响的补充临床和神经生物学数据。这一结果将显著提高我们对与精神病相关的罕见CNV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，结果将继续努力将病理生理学和医学上可操作的治疗干预与潜在的遗传学联系起来，对其他神经精神疾病患者有潜在的好处，这些患者具有相同基因或受相同或相关异常生物学过程影响的其他基因/途径的突变。