N-carbamylglutamate in the treatment of hyperammonemia

描述（由申请方提供）：本项目的总体目标是确定在丙酸血症（PA）、甲基丙二酸血症（MMA）、氨甲酰磷酸合成酶1缺乏症（CPSD）和鸟氨酸转氨甲酰酶缺乏症（OTCD）中使用N-氨甲酰-L-谷氨酸盐（NCG）治疗急性高氨血症是否会改变疾病的临床结局。具体目标是：1.确定NCG治疗重度、脑源性PA和MMA的急性高氨血症是否可改善神经发育结局，以及是否安全。2.确定NCG治疗急性高氨血症是否加速重度PA和MMA患者以及部分CPSD和OTCD患者的高氨血症消退和临床恢复，以及是否安全。3.确定在代谢稳定的患者中，3天NCG治疗对尿素生成的影响是否可预测目标1和2中观察到的结局。这是一项双盲，安慰剂对照试验，在全国七家儿童医院进行。目标1的主要结局指标是使用适合年龄的特定神经发育工具评估的神经认知发育。目标2的主要结局包括NCG对高氨血症缓解速度及其临床症状和住院时间的影响。目标3结局是评估NCG对尿素生成率的短期影响与NCG长期和急性临床环境中的临床应答之间的相关性，如目标1和2所确定。我们的假设是，NCG将改善这些疾病的临床结果。这些研究旨在为NCG的疗效和安全性提供科学证据，可用于扩大该药物的适应症，从而获得FDA批准。 公共卫生相关性：血液中氨水平升高会导致严重的脑损伤，发育障碍，并可能是致命的。N-乙酰谷氨酸（NAG）是肝脏中的一种小分子，对尿素循环至关重要，可使血氨水平低于对大脑有毒的水平。我们现在有强有力的初步证据表明，N-氨甲酰谷氨酸盐（Carbaglu），一种与NAG非常相似的化学物质，但与NAG不同，它不会在体内分解，可以模仿NAG的作用，降低患有许多遗传性代谢疾病的患者的氨水平。该项目将研究Carbaglu是否可以改善临床结果，减少或预防患有与高氨水平相关的四种不同遗传疾病的患者的氨脑损伤。如果结果证实了我们的假设，这些患者可以用Carbaglu治疗，以保持他们的氨水平在正常或接近正常水平，保护他们免受脑损伤。

DESCRIPTION (provided by applicant): The overall objective of this project is to determine whether treatment of acute hyperammonemia with N-carbamyl-L-glutamate (NCG) in propionic acidemia (PA), methylmalonic acidemia (MMA), carbamyl phosphate synthetase 1 deficiency (CPSD) and ornithine transcarbamylase deficiency (OTCD) changes the clinical outcome of disease. The specific aims are: 1. To determine whether NCG treatment of acute hyperammonemia in severe, neonatal-onset PA and MMA improves neurodevelopmental outcome, and whether it is safe. 2. To determine whether NCG treatment of acute hyperammonemia accelerates the resolution of hyperammonemia and clinical recovery in patients with severe PA and MMA and in those with partial CPSD and OTCD, and whether it is safe. 3. To determine whether, in metabolically stable patients, the effect of a 3-day NCG treatment on ureagenesis is predictive of the outcomes observed in Aims 1 and 2. This is a double blind, placebo controlled trial performed in seven children's hospitals across the country. The primary outcome measure for Aim 1 is neurocognitive development assessed using age-appropriate specific neurodevelopmental instruments. Primary outcomes of Aim 2 include the effect of NCG on the pace of resolution of hyperammonemia and its clinical symptoms and the length of hospitalization. The Aim 3 outcome is an assessment of the correlation between the short-term effect of NCG on ureagenesis rate and the clinical response to NCG long term and in acute clinical settings as determined by Aims 1 and 2. Our hypothesis is that NCG will improve clinical outcome in these disorders. These studies are designed to provide scientific evidence for NCG efficacy and safety which can be used to expand the indication of this drug, leading to FDA approval. PUBLIC HEALTH RELEVANCE: Elevated ammonia levels in the blood can cause severe brain damage, developmental disabilities and can be fatal. N-acetylglutamate (NAG) is a small molecule in the liver that is essential for the urea cycle, keeping blood ammonia levels below levels that are toxic to the brain. We now have strong preliminary evidence that N- carbamylglutamate (Carbaglu), a chemical that is very similar to NAG, but that, unlike NAG, is not broken down in the body, can mimic the effect of NAG to decrease ammonia levels in patients with a number of inherited metabolic diseases. This project will investigate whether Carbaglu can improve the clinical outcome and reduce or prevent brain damage from ammonia in patients with four different genetic diseases associated with high ammonia levels. If the results confirm our hypothesis, these patients can be treated with Carbaglu to keep their ammonia level at normal or close to normal levels, protecting them from brain damage.