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Principal Investigator: Kristofer S Fritz
Organization: MITOTHERAPEUTIX, LLC
Fiscal Year: 2023
Award: $273,918
Funding agency: National Institute on Alcohol Abuse and Alcoholism
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.
Terms: <4 hydroxynonenal><4-HNE cpd><4-hydroxy-2,3-nonenal><4-hydroxy-2-nonenal><4-hydroxynonen-2-al><APAP><Abscission><Acetamidophenol><Acetaminophen><Acetominophen><Acetylgalactosamine><Acute><Address><Adrenal Cortex Hormones><Alcohol Chemical Class><Alcohol Drinking><Alcohol abuse><Alcohol consumption><Alcohol toxicity><Alcoholic Liver Diseases><Alcohols><Animal Diseases><Animals><Behavioral><Binding><Blood Alcohol Content><Blood Serum><Blood alcohol level measurement><Body Weight><Caloric Intake><Carbamide><Chronic><Cirrhosis><Citric Acid Cycle><Complex><Consumption><Control Animal><Corticoids><Corticosteroids><Coupled><Dedications><Defect><Diet><Dose><Drug Therapy><Drugs><Elaqua XX><Electron Transport><Electrons><Energy Intake><EtOH abuse><EtOH drinking><EtOH use><Ethanol toxicity><Event><Excision><Extirpation><FADH2><FDA approved><Fatty Acids><Fatty Liver><Fibrosis><GI microbiome><GSSG><Glutathione Disulfide><Healthcare><Hepatic><Hepatic Cells><Hepatic Disorder><Hepatic Parenchymal Cell><Hepatocyte><Hospital Admission><Hospitalization><Human><Hydroxyacetanilide><Immunoblotting><Immunohistochemistry><Immunohistochemistry Cell/Tissue><Immunohistochemistry Staining Method><Individual><Inflammation><Injury to Liver><Intermediary Metabolism><Krebs Cycle><Lead><Link><Lipid Trafficking><Liver><Liver Cells><Liver Steatosis><Liver diseases><Medical><Medication><Metabolic><Metabolic Processes><Metabolism><Methylation><Mice><Mice Mammals><Mitochondria><Mitochondrial Proteins><Modality><Modeling><Modern Man><Molecular Interaction><Monitor><Morbidity><Morbidity - disease rate><Murine><Mus><N acetylgalactosamine><NADH><Negative Beta Particle><Negatrons><Obesity><Oxidation-Reduction><Oxidative Stress><Oxidative Stress Induction><Oxidized Glutathione><Oxpentifylline><Paracetamol><Pathologic><Pathology><Pb element><Pentoxifylline><Pharmaceutic Preparations><Pharmaceutical Preparations><Pharmacodynamics><Pharmacotherapy><Phase><Primates><Primates Mammals><Production><Proteins><Redox><Regimen><Removal><Research><Respiration><Risk><Route><STTR><Serum><Serum Albumin><Short interfering RNA><Small Business Technology Transfer Research><Small Interfering RNA><Source><Speed><Steatohepatitis><Surgical Removal><TCA cycle><Testing><Therapeutic><Therapeutic Intervention><Time><Toxic effect><Toxicities><Trental><Triacylglycerol><Tricarboxylic Acid Cycle><Triglycerides><Urea><Urea Carbamide><Ureaphil><Validation><Western Blotting><Western Immunoblotting><Work><adiposity><alcohol abuse therapy><alcohol abuse treatment><alcohol co-abuse><alcohol induced hepatic injury><alcohol induced liver disorder><alcohol induced liver injury><alcohol ingestion><alcohol intake><alcohol problem><alcohol product use><alcohol related liver disease><alcohol treatment><alcohol use><alcohol-associated liver disease><alcohol-induced hepatic dysfunction><alcohol-induced liver disease><alcohol-induced liver dysfunction><alcohol-mediated liver dysfunction><alcohol-mediated liver injury><alcohol-related liver disease><alcoholic beverage consumption><alcoholic drink intake><alcoholic liver injury><blood alcohol concentration><blood alcohol level><caloric dietary content><care burden><cirrhotic><corpulence><diets><digestive tract microbiome><drug candidate><drug treatment><drug/agent><electron transfer><enteric microbiome><ethanol abuse><ethanol consumption><ethanol drinking><ethanol induced hepatic injury><ethanol induced liver disorder><ethanol induced liver injury><ethanol ingestion><ethanol intake><ethanol liver disease><ethanol product use><ethanol use><ethanol-induced hepatic dysfunction><ethanol-induced liver disease><ethanol-induced liver dysfunction><ethanol-mediated liver dysfunction><ethanol-mediated liver injury><fat metabolism><fatty liver disease><feasibility testing><feeding><gastrointestinal microbiome><gut microbiome><gut-associated microbiome><hazardous alcohol use><health care><heavy metal Pb><heavy metal lead><hepatic body system><hepatic damage><hepatic disease><hepatic injury><hepatic organ system><hepatic steatosis><hepatopathy><hepatosteatosis><innovate><innovation><innovative><intervention therapy><intestinal biome><intestinal microbiome><knock-down><knockdown><lipid based nanoparticle><lipid metabolism><lipid nanoparticle><lipid transport><liver damage><liver disorder><liver injury><mitochondrial><mitochondrial dysfunction><mitochondrial metabolism><mortality><mouse model><murine model><new approaches><new drug target><new druggable target><new pharmacotherapy target><new therapeutic target><new therapy target><novel><novel approaches><novel drug target><novel druggable target><novel pharmacotherapy target><novel strategies><novel strategy><novel therapeutic target><novel therapy target><oxidation><oxidation reduction reaction><prevent><preventing><problem alcohol use><problem drinking><problematic alcohol consumption><problematic alcohol use><protein blotting><resection><respiratory><respiratory mechanism><risk minimization><siRNA><siRNA delivery><therapeutically effective><validations>