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

尿素循环障碍(UCD)是一组罕见但毁灭性的先天性代谢错误，从新生儿到成年都有很高的死亡率和发病率。UCD包括参与尿素生物合成的六种酶和两种膜转运体中的任何一种：N-乙酰谷氨酸合成酶(NAGS)缺乏；氨基甲酰磷酸合成酶I(CPSI)缺乏；鸟氨酸转氨甲基酶缺乏(OTCD)；精氨酸琥珀酸合成酶(AS)缺乏(瓜氨酸血症)；精氨酸琥珀酸裂解酶(AL)缺乏(精氨酸尿症)；精氨酸酶(ARG)缺乏(精氨酸血症)；高鸟血症、高氨血症、高钠尿症(HHH综合征)；在之前的赠款期间，我们在罕见疾病临床研究网络(RDCRN)内创建了尿素循环障碍联盟(UCDC)，并成功地启动了四个研究项目，旨在了解UCD的自然历史并开发新的治疗工具。目前，UCDC由8个美国站点组成，拥有一个由40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，该基金会是尿素循环障碍的患者倡导组织，并与业界合作开发这些疾病的创新疗法。在这项申请中，我们提出了3个完整的临床研究项目和一个试点项目。在临床项目中，我们将：1)继续我们的纵向研究，调查儿童和成人尿失禁的自然病史、发病率、死亡率和生物标志物；2)进行N-氨基甲酰谷氨酸酯的11/11期试验，以评估其对氨基甲酰磷酸1和鸟氨酸转氨甲基酶缺乏症患者尿失禁正常化的有效性；以及3) 使用结构MRI、功能MRI和磁共振波谱评估OTCD损伤的神经机制。在拟议的初步试点项目中，我们将研究一氧化氮合成的底物可用性以及精氨酸酶和精氨酸琥珀酸裂解酶缺乏症的相关发病机制。除了研究性学习，我们还将扩大和提升我们的教育和研究资源网站，并继续通过UCDC教育项目提供培训和职业发展机会。

Urea cycle disorders (UCD) are a group of 8 rare 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 (NAGS); Carbamyl phosphate synthase I (CPSI) deficiency; Ornithine transcarbamylase deficiency (OTCD); Argininosuccinate synthase (AS) deficiency (Citrullinemia); Argininosuccinate lyase (AL) deficiency (Argininosuccinic aciduria); Arginase (ARG) deficiency (Argininemia); Hyperornithinemia, hyperammonemia, homocitrullinuria (HHH) syndrome; and Citrullinemia type II. During the previous grant period we have created the Urea Cycle Disorders Consortium (UCDC) within the Rare Diseases Clinical Research Network (RDCRN) and have launched successfully four research projects aimed at understanding the natural history of UCD and developing new tools for treatment. Currently the UCDC consists of 8 U.S. sites with an interdisciplinary team of over 40 investigators and staff. The consortium works closely with the National Urea Cycle Disorders Foundation, the patient advocacy organization for urea cycle disorders and has collaboration with industry to develop innovative therapies for these disorders. We propose in this application 3 full clinical research projects and a pilot project. In the clinical projects we will: 1) Continue our longitudinal study that investigates the natural history, morbidity, mortality and biomarkers in children and adults with UCD; 2) Perform a Phase ll/lll trial of N-carbamylglutamate to assess its efficacy in normalizing ureagenesis in patients with carbamyl phosphate 1 and ornithine transcarbamylase deficiencies; and 3) Assess neural mechanisms of injury in OTCD using structural MRI, functional MRI, and magnetic resonance spectroscopy. In the proposed initial pilot project we will study substrate availability for nitric oxide synthesis and associated pathogenesis in arginase and argininosuccinate lyase deficiencies. 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 the UCDC educational programs.