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Novel Treatment for Alcohol-associated Liver Disease

Award Information
Agency: Department of Health and Human Services
Branch: National Institutes of Health
Contract: 1R41AA030517-01A1
Agency Tracking Number: R41AA030517
Amount: $273,918.00
Phase: Phase I
Program: STTR
Solicitation Topic Code: 350
Solicitation Number: PA22-178
Solicitation Year: 2022
Award Year: 2023
Award Start Date (Proposal Award Date): 2023-04-01
Award End Date (Contract End Date): 2024-03-31
Small Business Information
Cheshire, CT 06410-7118
United States
DUNS: 079732386
HUBZone Owned: No
Woman Owned: No
Socially and Economically Disadvantaged: No
Principal Investigator
 (303) 724-7932
Business Contact
Phone: (203) 240-9566
Research Institution
AURORA, CO 80045-2571
United States

 Nonprofit College or University

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.

* Information listed above is at the time of submission. *

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