Novel Treatment for Alcohol-associated Liver Disease

摘要 该I期TTR提案的具体目的是测试我们的siRNA药物改善肿瘤细胞增殖的可行性。 酒精相关性肝病（ALD）的病理学和进展。酒精消费仍然是主要的 是世界范围内肝脏病理学的主要原因，也是可预防疾病的最大来源之一， mortality.在美国，酒精滥用影响了1000多万人，是一个主要的医疗负担。的 ALD的根本原因是多因素的，包括肥胖、氧化应激和炎症，所有这些因素都 导致从脂肪变性到脂肪性肝炎、肝硬化和纤维化的病理进展。 有效的治疗方式针对ALD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肝脂肪变性的级联反应。 炎症和不可逆的肝损伤。酒精诱导的线粒体功能障碍是一个关键的驱动因素， 脂肪变性和相关代谢缺陷导致严重ALD。我们提出了治疗ALD的新方法 通过安全地增加肝脏中的线粒体代谢，并将在ALD的急性和慢性模型中测试这一点。 脂质被转运到肝脏，在那里它们在线粒体中通过细胞溶质β-氧化代谢， 其通过柠檬酸循环与电子传递链（ETC）和线粒体偶联 呼吸NADH和FADH 2是进入ETC的来自β-氧化的两种主要产物（NADH是 复合物I的底物和复合物II的FADH 2），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， 脂肪变性ETC的关键内源性负调节因子是MCJ蛋白（MCJ/DnaJC 15或甲基化- 受控J蛋白）。MCJ是一种线粒体蛋白，其通过结合至 复合体I我们的工作表明，去除MCJ似乎是安全的，并增加线粒体 呼吸而不引起氧化应激。我们已经开发了一种GalNAc（N-乙酰半乳糖胺）连接 特异性针对MCJ的siRNA药物。与GalNAc的缀合将siRNA引导至肝细胞，并提供 一条直接针对酒精中毒的路线验证siRNA治疗肝病的方法，两种GalNAc连接的siRNA FDA批准药物用于治疗肝病（Patisiran，脂质纳米颗粒配制的siRNA 和Givosiran，GalNAc缀合的siRNA）。 我们已经开发了一种领先的治疗剂，GalNAc连接的特异于MCJ的siRNA（MITO-1041），并验证了我们的研究。 使用许多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是人类、灵长类动物和小鼠MCJ的专有和特异性药物，允许快速IND启用 到时候再学习。然而，我们尚未在ALD小鼠模型中测试MITO-1041。 因此，我们本项目的具体目的是测试使用肝MCJ靶向siRNA的可行性， （MITO-1041）以改善酒精诱导的脂肪变性和相关病理。

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.