Targeting Integrin Alpha V Beta 3 By A Rationally Designed Protein For Chronic Liver Disease Treatment

Chronic Liver Diseases (CLD) are characterized by abnormal accumulation of collagen fibrils, neo-angiogenesis, and sinusoidal remodeling. Collagen deposition along with intrahepatic angiogenesis and sinusoidal remodeling alters sinusoid structure resulting in portal hypertension, liver failure, and other complications. Efforts were made to develop treatments for CLDs. However, the success of such treatments is limited and unpredictable. We report a strategy for CLD treatment by induction of integrin alpha(v)beta(3) mediated cell apoptosis using a rationally designed protein (ProAgio). ProAgio is designed to target integrin alpha(v)beta(3) at a novel site. Integrin alpha(v)beta(3) is highly expressed in activated Hepatic Stellate Cells (HSC), angiogenic endothelium, and capillarized Liver Sinusoidal Endothelial Cells (LSEC). ProAgio induces apoptosis of these disease causative cells. Tests with liver fibrosis mouse models demonstrate that ProAgio reverses liver fibrosis and relieves blood flow resistance by depleting activated HSC and capillarized LSEC. Our studies demonstrate an effective approach for CLD treatment.As activated hepatic stellate cells and liver sinusoidal endothelial cells express high levels of integrin alpha v beta 3, Turaga et al. present a strategy for treatment of chronic liver disease using their rationally designed protein (ProAgio) which targets integrin alpha v beta(3). They find that ProAgio -mediated apoptosis of these disease-associated cells reverses liver fibrosis and ameliorates intrahepatic vascular resistance in a mouse model