Novel Treatment for Alcohol-associated Liver Disease

酒精相关性肝病的新疗法

• 批准号: 10698605
• 负责人: Kristofer S. Fritz
• 金额: $ 27.39万
• 依托单位: MITOTHERAPEUTIX, LLC
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10698605
• 关键词: 4 hydroxynonenal; Acetaminophen; Acetylgalactosamine; Acute; Address; Adrenal Cortex Hormones; Alcohol abuse; Alcohol consumption; Alcoholic Liver Diseases; Alcohols; Animal Diseases; Animals; Behavioral; Binding; Blood alcohol level measurement; Body Weight; Chronic; Cirrhosis; Citric Acid Cycle; Complex; Consumption; Control Animal; Coupled; Dedications; Defect; Diet; Dose; Electron Transport; Electrons; Energy Intake; Ethanol toxicity; Event; Excision; FADH2; FDA approved; Fatty Acids; Fatty Liver; Fibrosis; Glutathione Disulfide; Healthcare; Hepatic; Hepatocyte; Hospitalization; Human; Immunohistochemistry; Individual; Inflammation; Lead; Link; Liver; Liver diseases; Medical; Metabolic; Metabolism; Methylation; Mitochondria; Mitochondrial Proteins; Modality; Modeling; Monitor; Morbidity - disease rate; Mus; NADH; Obesity; Oxidation-Reduction; Oxidative Stress; Oxidative Stress Induction; Pathologic; Pathology; Pentoxifylline; Pharmaceutical Preparations; Pharmacodynamics; Pharmacotherapy; Phase; Primates; Production; Proteins; Regimen; Research; Respiration; Risk; Route; Serum; Serum Albumin; Small Business Technology Transfer Research; Small Interfering RNA; Source; Speed; Steatohepatitis; Testing; Therapeutic; Therapeutic Intervention; Time; Toxic effect; Triglycerides; Urea; Validation; Western Blotting; Work; alcohol abuse therapy; care burden; drug candidate; fatty liver disease; feasibility testing; feeding; gut microbiome; innovation; knock-down; lipid metabolism; lipid nanoparticle; lipid transport; liver injury; mitochondrial dysfunction; mitochondrial metabolism; mortality; mouse model; new therapeutic target; novel; novel strategies; oxidation; prevent; respiratory; risk minimization; siRNA delivery; therapeutically effective

Abstract The Specific Aim of this Phase I TTR proposal is to test the feasibility of our siRNA drug to ameliorate the pathology and progression of alcohol-associated liver disease (ALD). Alcohol consumption remains a leading cause of hepatic pathology worldwide and is one of the greatest sources of preventable morbidity and mortality. In the U.S., alcohol abuse impacts over 10 million individuals and is a major healthcare burden. The underlying cause of ALD is multi-factorial, including obesity, oxidative stress, and inflammation, all of which contribute the pathological progression from steatosis to steatohepatitis, cirrhosis, and fibrosis. Effective therapeutic modalities targeting ALD remain critically absent. Targeting the underlying pathological mechanisms leading to alcohol-induced hepatic steatosis may prevent the cascade of events inducing inflammation and irreversible liver damage. Alcohol-induced mitochondrial dysfunction is a key driver of steatosis and related metabolic defects leading to severe ALD. We propose the novel approach of treating ALD by safely increasing mitochondrial metabolism in the liver and will test this in acute and chronic models of ALD. Lipids are transported to the liver where they are metabolized in mitochondria through cytosolic beta-oxidation, which is coupled through the citric acid cycle to the electron transport chain (ETC) and mitochondrial respiration. NADH and FADH2, are the two main products from beta-oxidation that feed into the ETC (NADH is substrate for Complex I and FADH2 for Complex II), therefore increasing ETC activity will increase beta- oxidation. Enhancing hepatic ETC activity could therefore speed up the degradation of fatty acids, preventing steatosis. A key endogenous negative regulator of the ETC is the MCJ protein (MCJ/DnaJC15 or Methylation- Controlled J protein). MCJ is a mitochondrial protein that negatively regulates ETC metabolism by binding to complex I. Our work demonstrates that removal of MCJ appears to be safe and increases mitochondrial respiration without inducing oxidative stress. We have developed a GalNAc (N-acetylgalactosamine) linked siRNA drug that is specific to MCJ. Conjugation to GalNAc directs the siRNA to liver hepatocytes and provides a direct route targeting ALD. Validating an siRNA approach to treating liver disease, two GalNAc linked siRNA drugs are approved by the FDA for treatment of liver diseases (Patisiran, lipid-nanoparticle formulated siRNA and Givosiran, GalNAc-conjugated siRNA). We have developed a lead therapeutic, GalNAc linked siRNA specific to MCJ (MITO-1041) and validated our siRNA approach to reducing steatosis and fibrosis in liver using many mouse models of fatty liver disease. MITO-1041 is proprietary and specific for human, primate, and mouse MCJ, allowing for rapid IND enabling studies when the time comes. However, we have not yet tested MITO-1041 in mouse models of ALD. Therefore, our Specific Aim of this project is to test the feasibility of using a hepatic MCJ targeted siRNA (MITO-1041) to ameliorate alcohol-induced steatosis and associated pathologies.

抽象的 该 I 期 TTR 提案的具体目标是测试我们的 siRNA 药物改善 酒精相关性肝病（ALD）的病理学和进展。酒精消费仍居首位 是全世界肝脏病理的病因，也是可预防发病率的最大来源之一 死亡。在美国，酗酒影响着超过 1000 万人，并且是一项重大的医疗负担。这 ALD 的根本原因是多因素的，包括肥胖、氧化应激和炎症，所有这些 促进从脂肪变性到脂肪性肝炎、肝硬化和纤维化的病理进展。 针对 ALD 的有效治疗方式仍然严重缺乏。针对潜在的病理 导致酒精诱导的肝脂肪变性的机制可能会阻止诱导事件的级联发生 炎症和不可逆的肝损伤。酒精引起的线粒体功能障碍是导致线粒体功能障碍的关键因素 脂肪变性和相关代谢缺陷导致严重的 ALD。我们提出治疗 ALD 的新方法 通过安全地增加肝脏中的线粒体代谢，并将在急性和慢性 ALD 模型中对此进行测试。 脂质被转运到肝脏，在那里它们通过细胞质β-氧化在线粒体中代谢， 通过柠檬酸循环与电子传递链 (ETC) 和线粒体耦合 呼吸。 NADH 和 FADH2 是 β-氧化作用进入 ETC 的两种主要产物（NADH 是 复合物 I 的底物和复合物 II 的 FADH2），因此增加 ETC 活性将增加 β- 氧化。因此，增强肝脏 ETC 活性可以加速脂肪酸的降解，从而防止 脂肪变性。 ETC 的一个关键内源性负调节因子是 MCJ 蛋白（MCJ/DnaJC15 或甲基化- 受控 J 蛋白）。 MCJ 是一种线粒体蛋白，通过结合来负向调节 ETC 代谢 复合物 I。我们的工作表明，去除 MCJ 似乎是安全的，并且会增加线粒体 呼吸而不引起氧化应激。我们开发了一种 GalNAc（N-乙酰半乳糖胺）连接的 MCJ 特异性的 siRNA 药物。与 GalNAc 结合可将 siRNA 引导至肝细胞并提供 针对 ALD 的直接途径。验证治疗肝病的 siRNA 方法，两种 GalNAc 连接的 siRNA FDA 批准用于治疗肝病的药物（Patisiran、脂质纳米颗粒配制的 siRNA） 和 Givosiran，GalNAc 缀合的 siRNA）。 我们开发了一种领先的治疗方法，GalNAc 连接的 siRNA 特异性针对 MCJ (MITO-1041)，并验证了我们的 使用多种脂肪肝疾病小鼠模型，采用 siRNA 方法减少肝脏脂肪变性和纤维化。 MITO-1041 是专有的，专门针对人类、灵长类动物和小鼠 MCJ，可实现快速 IND 启用 到时候就研究。然而，我们尚未在 ALD 小鼠模型中测试 MITO-1041。 因此，我们这个项目的具体目标是测试使用肝脏 MCJ 靶向 siRNA 的可行性 (MITO-1041) 改善酒精引起的脂肪变性和相关病理。