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

基本信息

批准号：
10378282
负责人：
Shyamasundaran Kottilil
金额：
$ 98.52万
依托单位：
MITOPOWER LLC
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-25 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10378282
关键词：
Acute Renal Failure with Renal Papillary Necrosis Address Aging Alcoholic Liver Diseases Alcohols Animal Model Biogenesis Canis familiaris Cell physiology Clinical DNA Damage Development Dose Formulation Functional disorder Funding Gene Expression Goals Hemodialysis Hepatic Hepatocyte Hepatorenal Syndrome Histology Hospitalization Human Immune Immunomodulators Impairment In Vitro Inflammatory Injury to Kidney Intravenous Kidney Kidney Failure Liver Liver Cirrhosis Liver diseases Mediating Metabolism Mitochondria Nicotinamide adenine dinucleotide Organ failure Outcome Oxidative Stress Patient-Focused Outcomes Patients Pharmaceutical Preparations Pharmacodynamics Pharmacology Pharmacology and Toxicology Phase Phase I Clinical Trials Population Preparation Process Rattus Renal function Role Safety Serum Small Business Innovation Research Grant Supplementation Therapeutic Therapeutic Index Time Tissues Toxic effect Whole Blood Work acute toxicity base dihydronicotinamide first-in-human genotoxicity healthy volunteer human study improved improved outcome in vivo ischemic injury lipid biosynthesis liver injury liver transplantation mitochondrial dysfunction mortality nicotinamide-beta-riboside novel therapeutics oxidation prevent research clinical testing riboside small molecule therapeutics standard of care systemic inflammatory response tissue culture

项目摘要

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.

与酒精性肝病相关的肝肾上腺综合征的新型治疗抽象的在美国，酒精性肝病（ALD）每年可导致超过400,000个住院患有急性肾脏损伤（HRS-AKI）的肝烯综合征的患者。目前没有治疗专门解决细胞功能障碍和全身性炎症反应的选项，导致通过直接酒精介导的线粒体功能障碍和氧化应激介导的进行性器官衰竭毒性。这会导致肝细胞和肾功能受损，器官破坏，并需要保护性肾脏和肝疗法的目的是改善患有HRS-AKI的患者的临床结果。烟酰胺腺嘌呤二核苷酸（NAD+）是肝脏和肾脏与衰老有关的疾病的标志。在ALD中发现了NAD+的水平下降和合成受损，伴随着从头增加通过酒精在NAD+耗竭和细胞功能受损。 NAD+补充NAD+前体烟酰胺核苷（NR）逆转酒精诱导的变化通过增加组织培养中的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，NR补充NAD+已有证明可以改善肝组织学，减少肝损伤并保护肾脏免受缺血性损伤和DNA 损害阻止肾脏损伤的逐渐恶化。 2,4二氢酮二胺核苷（NRH），最近鉴定出高度有效的NAD+前体，始终在更大程度上增加细胞内NAD+水平肝脏和肾脏中的NR在血清中稳定，此外，还充当高度有效的免疫调节剂系统性炎症状态。鉴于患者的NAD+水平的NAD+水平显着耗尽使用ALD，NRH有可能逆转或防止ALD患者组合HRS-AKI的进展使用护理标准。在这项快速的研究中，我们将完成对专有的辅助研究 NRH的静脉配方MP04，然后进行1期临床试验，以研究其安全性和耐受性在人类中。这项工作的结果将是与ALD相关的HRS的新型治疗方法。