Novel therapy for alcoholic liver disease-associated hepatorenal syndrome

酒精性肝病相关性肝肾综合征的新疗法 摘要 在美国，酒精性肝病(ALD)每年导致超过40万人住院，其中一部分 发生肝肾综合征并急性肾损伤(HRS-AKI)的患者。目前还没有治疗方法 具体解决导致细胞功能障碍和全身炎症反应的选项 直接酒精介导的线粒体功能障碍和氧化应激所致的进行性器官衰竭 毒性。这会导致肝细胞和肾功能受损，器官衰竭恶化，需要采取保护措施 肾脏和肝脏治疗，目的是改善HRS-AKI患者的临床结果。 烟酰胺腺嘌呤二核苷酸(NAD)是与衰老有关的肝和肾脏疾病的标志。 ALD患者NAD水平降低和合成受损，并伴有新生能力增加 酒精在NAD耗竭和线粒体氧化损伤中的作用 细胞功能受损。NAD补充NAD前体烟酰胺核苷(NR)可逆转 酒精通过增加组织培养中NAD水平，增强线粒体氧化， 线粒体的生物发生和基因表达。在动物模型中，NAD与NR的补充一直是 改善肝脏组织学，减少肝脏损伤，保护肾脏免受缺血损伤和DNA 防止肾脏损伤的进行性恶化的损害。2，4-二氢烟酰胺核苷(NRH)，新近发现的 已确定的高效力NAD前体，持续增加细胞内NAD水平的程度高于 在肝脏和肾脏中，NR在血清中稳定，此外，它还作为一种高效的免疫调节剂来抑制 全身炎症状态。鉴于患者肝脏和肾脏中NAD水平的显著耗竭 对于ALD，NRH联合应用有可能逆转或阻止ALD患者HRS-AKI的进展 以护理的标准。在此快速通道研究中，我们将完成对我们的专有技术的支持IND的研究 静脉注射NRH，MP04，随后进行1期临床试验，以研究其安全性和耐受性 在人类身上。这项工作的结果将是ALD相关HRS的一种新的治疗方法。

Novel therapy for alcoholic liver disease-associated hepatorenal syndrome Abstract Alcoholic liver disease (ALD) results in over 400,000 hospitalizations each year in the US, with a portion of these patients developing hepatorenal syndrome with acute kidney injury (HRS-AKI). There are no current therapeutic options that specifically address the cellular dysfunction and systemic inflammatory response that leads to progressive organ failure mediated by mitochondrial dysfunction and oxidative stress by direct alcohol-mediated toxicity. This leads to impaired hepatocyte and renal function, worsening organ failure, and the need for protective renal and hepatic therapies with the goal of improving clinical outcomes for patients who develop HRS-AKI. Nicotinamide adenine dinucleotide (NAD+) is a hallmark of aging-related disease for the liver and kidney. Decreased levels and impaired synthesis of NAD+ are found in ALD accompanied by increased de novo lipogenesis and impaired mitochondrial oxidation made possible by the role of alcohol in NAD+ depletion and impaired cellular function. NAD+ supplementation with the NAD+ precursor nicotinamide riboside (NR) reverses alcohol-induced changes by increasing NAD+ levels in tissue culture, enhancing mitochondrial oxidation, mitochondrial biogenesis, and gene expression. In animal models, NAD+ supplementation with NR has been shown to improve liver histology, reduce liver injury and protect the kidneys against ischemic injury and DNA damage preventing progressive worsening of renal injury. 2,4 dihydronicotinamide riboside (NRH), , a recently identified highly potent NAD+ precursor, consistently increases intracellular NAD+ levels to a greater extent than NR in liver and kidney, is stable in serum, and in addition acts as a highly potent immune modulator to dampen the systemic inflammatory state. Given the significant depletion in NAD+ levels in both liver and kidney in patients with ALD, NRH has the potential to reverse or prevent progression of HRS-AKI in ALD patients in combination with the standard of care. In this Fast Track study, we will complete IND-enabling studies of our proprietary intravenous formulation of NRH, MP04, followed by a Phase 1 clinical trial to investigate its safety and tolerability in humans. The outcome of this work will be a novel therapeutic for ALD-associated HRS.