Chronic liver disease affects approximately 3 million people and leads to more than 42,000 deaths each year in the United States. Fibrosis is the outcome of almost all chronic liver diseases. It is due to a dynamic scarring process caused by the response of the body to liver injury in a similar way that injury causes scarring in the skin or other organs through the deposition of collagen and other extracellular matrix components. Fibrosis that is so extensive that the liver is no longer functional results in cirrhosis – the main cause of death from chronic liver disease. Resolution of liver fibrosis has been shown in animal models and in patients after treatment and/or removal of a causative agent but there are no approved agents that act to prevent or reverse fibrosis.
Mounting data implicate galectin-3 as a causal factor in liver fibrosis. Compared to wild type mice, galectin-3 deficient mice were protected from liver fibrosis from carbon tetrachloride exposure or bile duct ligation despite equivalent injury. Inhibition of galectin-3 expression with small interfering RNA had a therapeutic effect in the carbon tetrachloride mouse model of acute liver disease. In a bile duct ligation mouse model of chronic liver disease, galectin-3 expression was found to be induced in hepatic stellate cells that give rise to the fibrogenic myofibroblasts. Systemic and hepatic vein levels of galectin-3 were increased in patients with alcoholic liver cirrhosis and the levels were found to be negatively correlated with liver function.
MandalMed scientists and collaborators are testing MM-003, a dominant negative protein inhibitor of galectin-3, in animal models of liver disease to determine whether treatment can prevent and reverse liver fibrosis.