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.
Public Health Relevance Statement: Public Health Relevance: Heprotech Inc. develops liver-protective therapeutics for the treatment of acute and chronic liver diseases such as alcoholic steatohepatitis. Alcoholic liver disease is a highly prevalent and costly liver disease marked by chronic progression of steatotic and fibrotic liver injury marked by acute episodes of inflammation termed acute alcoholic steatohepatitis, which commonly require hospitalization and critical care depending on their severity. If not treated, recurrent steatohepatitis leads to progressive fibrosis, cirrhosis, and ed-stage liver disease, which is often fatal if transplantation is not performed. There are no approved therapies. Instead acute exacerbations are managed by off-label use of nonspecific immunosuppressants and antioxidants that are only modestly effective and are only available to those patients meeting narrowly defined eligibility criteria. As a result, most patients remain inadequately or completely untreated. For chronic alcoholic liver disease, there are no preventative therapies that reduce the frequency or severity of acute alcoholic steatohepatitis episodes. Scientists at Heprotech previously discovered a novel role for hepatocyte gap junction intercellular communication in pathogenesis of acute and chronic liver diseases including drug-induced liver injury and diet- induced nonalcoholic steatohepatitis. We have developed a portfolio of small molecule gap junction inhibitors to block this communication pathway and are developing them as first-in-class hepatoprotectants. More recently, we discovered that inhibition of gap junction communication also limits liver injury and inflammation resulting from alcohol ingestion. Therefore, Heprotech now seeks funding to adapt our first-in-class hepatoprotectants to the treatment of the important and underserved problem of acute and chronic alcoholic liver disease.
Project Terms: Acetaminophen; Acute; Acute Alcoholic Hepatitis; Acute Hepatitis; acute liver injury; Adrenal Cortex Hormones; Affect; Alcohol consumption; Alcohol-Induced Disorders; Alcoholic Hepatitis; Alcoholic Intoxication; Alcoholic Liver Diseases; Alcohols; Animal Model; Antioxidants; Ascites; base; Biochemical; Cells; Cessation of life; Chronic; chronic alcohol ingestion; chronic liver disease; Cirrhosis; Clinical; Communication; connexin 32; Connexins; Coupled; Critical Care; Cytosol; Data; design; Development; Diet; Economic Burden; Eligibility Determination; Ethanol; Fatty Change; Fibrosis; Frequencies (time pattern); Funding; Gap Junctions; gastrointestinal infection; Genetic; Goals; Grant; Heavy Drinking; Hemorrhage; Hepatic; Hepatocyte; Hepatoprotective Agent; Hepatotoxicity; Hospitalization; Immune; Immunosuppressive Agents; improved; Infection; Inflammation; inhibitor/antagonist; Injury; intercellular communication; Label; Lead; Liver; Liver diseases; liver inflammation; liver injury; liver transplantation; Mediator of activation protein; Medical; meetings; Metabolism; Modeling; Morbidity - disease rate; Mortality Vital Statistics; mouse model; Mus; National Institute on Alcohol Abuse and Alcoholism; nonalcoholic steatohepatitis; novel; novel therapeutic intervention; Organ; Outcome; outcome forecast; Oxidative Stress; Pathogenesis; Pathway interactions; Patients; Pentoxifylline; Pharmaceutical Preparations; Phase; Play; pre-clinical; preclinical study; Primary carcinoma of the liver cells; problem drinker; Program Development; programs; Proteins; public health relevance; Recurrence; response; Risk; Role; Scientist; Severities; Signal Transduction; Small Business Innovation Research Grant; small molecule; Staging; standard of care; Steatohepatitis; Therapeutic; Tissues; Transplantation; Treatment Efficacy; treatment strategy; Validation; Wild Type Mouse; Work
