Rare Diseases Clinical Research Consortia (RDCRC) for the RDCR Network

描述（由申请人提供）：尿素循环障碍（UCD）是一组8种罕见（总发病率1：30，000）但具有破坏性的先天性代谢缺陷，从新生儿期到成年期具有高死亡率和发病率。UCD包括参与尿素生物合成的六种酶和两种膜转运蛋白中任何一种的缺陷：N-乙酰谷氨酸合酶缺陷（NAGSD）;磷酸氨甲酰合酶I缺陷（CPS 1D）;鸟氨酸转氨甲酰酶缺陷（OTCD）;精氨酸琥珀酸合酶缺陷（ASSD）;精氨酸琥珀酸裂解酶缺陷（ASLD）;精氨酸酶（ARGID）缺陷（精氨酸血症）;高鸟氨酸血症、高氨血症、高瓜氨酸尿（HHH）综合征;和瓜氨酸血症II型。十年前，我们创建了尿素循环障碍联盟（UCDC），作为罕见疾病临床研究网络（RDCRN）的首批成员之一，随后进行了11项研究方案，旨在了解UCD的自然史，开发发病率的生物标志物和测试新疗法。目前，UCDC在美国有14个站点，加拿大和欧洲，拥有一支由60多名调查人员和工作人员组成的跨学科团队。该联盟与国家尿素循环障碍基金会密切合作，该基金会是UCD的患者倡导组织，并与业界合作开发针对这些疾病的创新疗法。我们在本申请中提出了3个完整的临床研究项目和3个试点项目。在临床项目中，我们将：1）扩大我们的研究，调查儿童和成人UCD的自然史，发病率，死亡率和生物标志物; 2）进行无机亚硝酸盐的II期试验，以评估纠正UCD的疗效。 一氧化氮缺乏及其在ASLD中的后果;和3）使用神经心理学测试结合结构MRI、功能MRI和磁共振波谱法评估OTCD、ASLD和ASSD中损伤的神经和认知机制。在拟议的试点项目中，我们将研究NexGen测序用于NAGSD，CPS 1D和OTCD的新生儿筛查;进行脲酶抑制剂试验以减少N积累;并使用DMCC维持的接触登记研究临床指南的依从性。除了研究研究，我们将扩大和加强我们的教育和研究资源的网站，并继续通过我们的教育计划提供培训和职业发展机会。

DESCRIPTION (provided by applicant): Urea cycle disorders (UCD) are a group of 8 rare (overall incidence 1:30,000) but devastating inborn errors of metabolism that carry a high mortality and morbidity from the newborn period through adulthood. UCD include deficiencies in any of the six enzymes and two membrane transporters involved in urea biosynthesis: N-acetylglutamate synthase deficiency (NAGSD); Carbamyl phosphate synthase I deficiency (CPS1D); Ornithine transcarbamylase deficiency (OTCD); Argininosuccinate synthase deficiency (ASSD); Argininosuccinatelyase deficiency (ASLD); Arginase (ARGID) deficiency (Argininemia); Hyperornithinemia, hyperammonemia, homocitrullinuria (HHH) syndrome; and Citrullinemia type II . A decade ago we created the Urea Cycle Disorders Consortium (UCDC) as one of the first members of the Rare Diseases Clinical Research Network (RDCRN) and have subsequently conducted 11 research protocols aimed at understanding the natural history of UCD, developing biomarkers of morbidity and testing novel therapies. Currently the UCDC consists of 14 sites in the U.S., Canada and Europe with an interdisciplinary team of over 60 investigators and staff. The consortium works closely with the National Urea Cycle Disorders Foundation, the patient advocacy organization for UCD and has collaborations with industry to develop innovative therapies for these disorders. We propose in this application 3 full clinical research projects and 3 pilot projects. In the clinical projects we will: 1) Expand our longitudina study that investigates the natural history, morbidity, mortality and biomarkers in children and adults with UCD; 2) Perform a Phase II trial of inorganic nitrites to assess efficacy in correcting nitric oxide deficiency and its consequences in ASLD; and 3) Assess neural and cognitive mechanisms of injury in OTCD, ASLD and ASSD using neuropsychological testing combined with structural MRI, functional MRI, and magnetic resonance spectroscopy. In the proposed pilot projects we will investigate NexGen sequencing for newborn screening of NAGSD, CPS1D and OTCD; perform a trial of urease inhibitors to decrease N accumulation; and use the DMCC maintained contact registry to study compliance with clinical guidelines. In addition to the research studies, we will expand and enhance our website for educational and research resources and continue to provide training and career development opportunities through our educational programs.