Biologic Inhibitor of Galectin-3 for Liver Fibrosis

PROJECT SUMMARY ABSTRACT Chronic liver disease affects approximatelymillion people in the United States and leads to more thandeaths each yearThe overall goal of this project is to develop a protein biologicMMthat acts by inhibition of galectinas a therapy for prevention and treatment of chronic liver fibrosisFibrosis is the outcome of almost all chronic liver diseasesIt 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 matrixECMcomponentsFibrosis that is so extensive that the liver is no longer functional results in cirrhosisthe main cause of death from chronic liver diseaseResolution 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 fibrosisMounting data implicate galectinas a causal factor in liver fibrosisCompared to wild type micegalectindeficient mice were protected from liver fibrosis from carbon tetrachloride exposure or bile duct ligationBDLdespite equivalent injuryInhibition of galectinexpression with small interferingsiRNA had a therapeutic effect in the carbon tetrachloride mouse model of acute liver diseaseIn the BDL mouse model of chronic liver diseasegalectinexpression was induced in hepatic stellate cellsHSCsthat give rise to the fibrogenic myofibroblastsSystemic and hepatic vein levels of galectinwere increased in patients with alcoholic liver cirrhosis and the levels were negatively correlated with liver functionWe postulate that inhibition of galectinby MMwill have a preventative effect on the development of liver fibrosiswill be therapeutic for chronic liver diseaseand will be safe for chronic useThe overall goal in Phase I is to obtain evidence of the potential efficacy of MMa biologic inhibitor of galectinfor therapy of chronic liver fibrosisThere are two Specific Aims for Phase IAimDetermine the effect of MMon profibrotic activity of primary human hepatic stellate cellsand macrophages in vitroAimDetermine the anti fibrotic potential of MMin mouse models of liver fibrosisADetermine efficacy in preventing and treating liver fibrosis in a mouse bile duct ligationBDLmodel of fibrosisBDetermine efficacy in preventingtreatingand reversing liver fibrosis in a mouse carbontetrachlorideCClmodel of fibrosis PROJECT NARRATIVE Chronic liver disease affects approximatelymillion people in the United States and leads to more thandeaths each yearThe overall goal of this project is to develop a protein biologicMMthat acts by inhibition of galectinas a therapy for prevention and treatment of chronic liver fibrosis