Novel Treatment for Alcohol-associated Liver Disease

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.