Nitric Oxide Supplementation as a Therapeutic Intervention in Argininosuccinate Lyase Deficiency

精氨酸琥珀酸酶缺乏症(ASLD)已被美国疾病控制与预防中心(UCDC)证明具有不同于其他尿素循环障碍的独特的临床和生理特征。ASLD患者约占UCD疾病的15%-20%，与其他UCD患者相比，他们的认知结果、肝脏疾病和血管问题相对较差。该联盟成员的研究已经清楚地证明了ASL在一氧化氮(NO)的产生中具有组织和分子特有的作用。作为ASS、ASL和eNOS底物通道复合体的一部分，我们已经证明ASL缺陷的细胞失去了产生足够NO的能力。这意味着该酶在NO的产生中既有动力学作用，也有结构作用。这项提案将解决使用合成的NO供体绕过这个复合体的效果。我们还表明，在有高血压症状的患者中，高血压的改善和认知改善的趋势在没有供体治疗的情况下发生。在这种治疗被接受在ASLD或其他UCD患者中广泛使用之前，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，并研究血管调节在治疗和非治疗中的作用以及神经认知效应。如果成功，这将导致一种治疗UCDs患者的新工具，解决UCDC纵向研究和联盟成员确定的一些并存问题。

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.