Development of Gap Junction Inhibition Therapy for Alcoholic Liver Disease

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 DESCRIPTION (provided by applicant): Alcoholic liver disease is a highly prevalent and costly condition affecting millions of people globally. Alcohol results in high morbidity and mortality an is responsible for nearly 4% of all deaths worldwide. Despite the tremendous societal and economic burden, there is no approved therapeutics for alcoholic liver disease. Instead, the standard of care involves off-label administration of nonspecific corticosteroids, immunosuppressants, and antioxidants. There is a desperate need for liver-specific therapeutics that can be used to treat acute and chronic alcoholic liver disease. Heprotech was founded to commercialize therapeutics based on inhibition of gap junction communication in the liver. We have demonstrated that liver-specific gap junctions composed of connexin 32 (Cx32) are essential to the pathogenesis of acute and chronic liver injury. We first showed that inhibitors of Cx32 gap junctions protect and rescue mice from drug-induced hepatotoxicity. Next we found that these Cx32 gap junction inhibitors were protective in diet-induced nonalcoholic steatohepatitis. Most recently, our preliminary results suggest Cx32 gap junctions are also essential for alcohol-induced liver injury. The overall goal of this Phase I SBIR grant is to defin the appropriate clinical context for inhibiting Cx32 gap junctions for protection against alcohol-induced liver injury. In aim 1, we will compare acute and chronic alcohol-induced liver injury in wild type and connexin 32 deficient mice. This will delineate whether the novel Cx32 target is important in acute and/or chronic alcohol-induced liver injury. In aim 2, we will investigate our lead Cx32 small molecule inhibitor in acute and chronic alcohol-induced liver injury. The anticipated outcome of this effort is clarification of whether Cx32 is important in acute injury, chronic injury, or both. Secondly, the proposed work will provide early evidence that small molecule inhibition of Cx32 gap junctions is a viable therapeutic strategy for treatment of alcoholic liver disease. These results will inform the design of focused preclinical studies that will be performed during Phase II of this SBIR program.