Nitric Oxide Supplementation as a Therapeutic Intervention in Argininosuccinate Lyase Deficiency

精氨酸琥珀酰裂解酶缺乏症（ASLD）已被UCDC证明在临床和生理行为上具有不同于其他尿素循环障碍的独特特征。约占UCD疾病的15-20%，ASLD患者的认知结果，肝脏疾病和血管问题比其他UCD相对更差。联盟成员的工作已经清楚地证明了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的底物通道复合物的一部分，我们已经表明ASL缺陷的细胞失去了产生足够NO的能力。这意味着NO生产中酶的动力学和结构作用。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，在高血压症状患者中，NO供体治疗可改善高血压，并有改善认知能力的趋势。在这种治疗被广泛用于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研究这些患者的表型，并研究血管调节治疗和关闭治疗以及神经认知效应。如果成功，这将导致一个新的工具，用于治疗UCD患者，解决UCDC纵向研究和联盟成员确定的一些合并症。

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.