Addressing liver fibrosis by TRAIL targetied to hepatic stellate cells

Liver fibrosis is considered as an end stage liver diseases and the primary cause of need for a liver transplant. The development of liver fibrosis is associated with progressive chronic liver disease. The best anti-fibrotic therapy is the elimination of the underlying disease process. In situations in which treating the underlying etiology is not possible, a specific anti-fibrotic therapy would be highly desirable. To date, many specific anti-fibrotic treatments have been tried, but the lack of overall efficiency and the cytotoxicity associated with these treatments form a barrier for their use in the clinic. The elaboration of the underlying pathophysiology of liver fibrosis showed that, despite the complex nexus of liver injury and the fibrotic process, activated Hepatic Stellate Cells (HSC) play a central role both as a causative and as a effector cell. Therefore, research focusing on the targeted elimination of activated HSCs as the first step in natural resolution of liver fibrosis is warranted. In this research we address this issue by TRAIL targeting to HSCs. Earlier studies have shown that the increase in TRAIL receptors on the surface of HSCs during activation is associated with an increase in HSC susceptibility to the TRAIL apoptosis effect. However, the short half-life of TRAIL in vivo and the development of anti-apoptotic signaling mechanisms that cause TRAIL resistance in activated HSCs have proven to be a major hurdle in enabling the therapeutic application of TRAIL as an option in treating liver fibrosis. This thesis deals with the application of targeting TRAIL genes and proteins as a novel technology having the potential to successfully treat liver fibrosis.