Novel therapy for alcoholic liver disease-associated hepatorenal syndrome

酒精性肝病相关肝肾综合征的新疗法 摘要 酒精性肝病（ALD）导致美国每年超过40万人住院，其中一部分人 发生肝肾综合征伴急性肾损伤（HRS-AKI）的患者。目前没有治疗方法 专门解决导致细胞功能障碍和全身炎症反应的选择 线粒体功能障碍介导的进行性器官衰竭和直接酒精介导的氧化应激 毒性这导致肝细胞和肾功能受损，器官衰竭恶化，需要保护性治疗。 肾脏和肝脏治疗，旨在改善发生HRS-AKI患者的临床结局。 烟酰胺腺嘌呤二核苷酸（NAD+）是肝脏和肾脏衰老相关疾病的标志。 在ALD中发现NAD+的水平降低和合成受损，伴有新生NAD+的增加。 脂肪生成和受损的线粒体氧化可能是由于酒精在NAD+消耗中的作用， 细胞功能受损用NAD+前体烟酰胺核苷（NR）补充NAD+逆转了 通过增加组织培养中NAD+水平，增强线粒体氧化， 线粒体生物发生和基因表达。在动物模型中，NAD+补充NR已经被证实是有效的。 显示改善肝脏组织学，减少肝损伤，保护肾脏免受缺血性损伤和DNA 防止肾损伤进行性恶化的损害。2，4-二氢烟酰胺核苷（NRH）是近年来发现的一种新的 鉴定出的高效NAD+前体，一致地增加细胞内NAD+水平， NR在肝脏和肾脏中，在血清中稳定，此外还作为一种高效的免疫调节剂， 全身炎症状态。考虑到患者肝脏和肾脏中NAD+水平的显著消耗， 与ALD联合，NRH有可能逆转或预防ALD患者的HRS-AKI进展， 按照护理标准。在这项快速通道研究中，我们将完成我们的专利产品的IND启用研究， NRH，MP 04的静脉内制剂，随后进行I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一种新的治疗ALD相关的HRS。

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.