Nitric Oxide Supplementation as a Therapeutic Intervention in Argininosuccinate Lyase Deficiency

补充一氧化氮作为精氨基琥珀酸裂解酶缺乏症的治疗干预措施

• 批准号: 8858725
• 负责人: MARK L. BATSHAW
• 金额: $ 10万
• 依托单位: CHILDREN'S RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-25 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8858725
• 关键词: Accounting; Address; Antihypertensive Agents; Arginine; Argininosuccinate lyase deficiency; Behavior; Biochemical; Biology; Blood Pressure; Blood Vessels; Brain; Bypass; California; Case Study; Cells; Characteristics; Child; Clinical; Clinical Research; Cognitive; Cognitive deficits; Cohort Analysis; Comorbidity; Complex; Cross-Over Studies; Data; Defect; Diagnosis; Dilatation - action; Disease; Distal; Dose; Double-Blind Method; Drug Formulations; Endothelium; Enzymes; Equipment and supply inventories; Generations; Genotype; Hepatic Vascular Disorder; Human; Hyperammonemia; Hypertension; Impairment; Inpatients; Intelligence; Intelligence quotient; Kinetics; Lead; Liver; Liver diseases; London; Longitudinal Studies; Measures; Mediating; Memory impairment; Modeling; Molecular; Morbidity - disease rate; Mus; Natural History; Neonatal Screening; Neurocognitive; Neurons; Nitrates; Nitric Oxide; Nitric Oxide Donors; Nitric Oxide Synthase; Nitrites; Outcome; Pathogenesis; Patient observation; Patients; Pharmaceutical Preparations; Phenotype; Physiological; Placebo Control; Placebos; Plasma; Production; Randomized; Rare Diseases; Recurrence; Refractory; Regulation; Research Personnel; Role; Safety; Short-Term Memory; Signaling Molecule; Sodium Nitrite; Source; Structural Models; Supplementation; Testing; Therapeutic Intervention; Tissues; Translating; Vascular Endothelium; Verbal Learning; Work; base; behavior test; brachial artery; endothelial dysfunction; enzyme activity; executive function; extracellular; gene therapy; hepatic ureagenesis; improved; member; mouse model; neurogenesis; neuropsychological; novel; pilot trial; prevent; stable isotope; tool; treatment strategy; trend; urea cycle

Argininosucciniclyase deficiency (ASLD) has been shown by the UCDC to have unique characteristics in clinical and physiologic behavior from the other urea cycle disorders. Accounting for around 15-20% of UCD disorders, ASLD patients have relatively worse cognitive outcomes, hepatic disorders, and vascular problems than other UCDs. Work by consortium members has clearly demonstrated a tissue and molecular specific role for ASL in the generation of nitric oxide (NO). As part of a substrate channeling complex involving ASS, ASL, and eNOS, we have shown that cells with defective ASL lose the ability to generate sufficient NO. This implies both a kinetic and structural role for the enzyme in NO production. This proposal will address the effect of bypassing this complex using a synthetic NO donor. We have also shown that in a hypertensive symptomatic patient that improvement in hypertension occurred and trends toward cognitive improvement occurred with NO donor treatment. Before this treatment would be accepted for widespread use in ASLD or other UCD patients an in depth double-blind placebo-controlled crossover study needs to be conducted. This proposed study will phenotype these patients in depth and study vaso-regulation on and off therapy as well as neurocognitive effects. If successful this would lead to a new tool for the treatment of patients with UCDs addressing some of the comorbidities identified by the UCDC longitudinal study and consortium members.

UCDC 已证明精氨基琥珀酸裂解酶缺乏症 (ASLD) 在临床和生理行为方面具有与其他尿素循环障碍不同的独特特征。 ASLD 患者约占 UCD 疾病的 15-20%，与其他 UCD 患者相比，其认知结果、肝脏疾病和血管问题相对较差。联盟成员的工作清楚地证明了 ASL 在一氧化氮 (NO) 生成中的组织和分子特异性作用。作为涉及 ASS、ASL 和 eNOS 的底物通道复合体的一部分，我们已经证明，有缺陷的 ASL 细胞失去产生足够 NO 的能力。这意味着该酶在 NO 产生中具有动力学和结构作用。该提案将解决使用合成 NO 供体绕过该复合物的影响。我们还表明，在有高血压症状的患者中，NO 供体治疗后高血压有所改善，并且认知能力有改善的趋势。在这种治疗被广泛应用于 ASLD 或其他 UCD 患者之前，需要进行深入的双盲安慰剂对照交叉研究。这项拟议的研究将深入对这些患者进行表型分析，并研究治疗期间和治疗期间的血管调节以及神经认知效应。如果成功，这将带来一种治疗 UCD 患者的新工具，解决 UCDC 纵向研究和联盟成员确定的一些合并症。