This application addresses broad Challenge Area (04): Clinical Research and specific Challenge Topic, 04- AA-101: Medication Development for Hepatic Fibrosis. Hepatic fibrosis (HF), a group of incurable liver disease with high mortality rate, is characterized by inflammatory cell infiltration, fibroblast proliferation, and excessive deposition of extracellular matrix proteins in liver parenchyma. There are million people around the world affected by HF. In the U.S. alone, 300,000 suffer from this disease. Of these more than 30,000 die annually, about the same number as die from breast cancer, more than the number of deaths from ovarian cancer or prostate cancer and forty times more than those who die from cystic fibrosis. There is no effective treatments for HF. Hence there is an urgent need to develop therapeutic agents that delay or reverse HF. Accumulating evidence indicates that TGF-B plays an important role in the pathogenesis of HF. TGF-B antagonists appear to be potentially important therapeutic agents for HF. We recently developed a synthetic TGF-B peptide antagonist (termed TGF-B peptantagonist) which antagonizes TGF-B activity in cultured cells. Topical application of gel containing TGF-B peptantagonist promotes wound healing and attenuates fibrosis in standard animal skin injury models. The use of TGF-? peptantagonist for treating HF is limited by its poor solubility in aqueous solution at neutral pH. We have developed a novel TGF-B peptantagonist derivative with increased solubility, long plasma half-life, and potent antagonist activity. They should be effective for treating HF by parenteral administration. Preliminary studies indicate that a pegylated TGF-?B peptantagonist (PEG-TGF-? peptantagonist) we have recently developed, which has excellent solubility, a long plasma half-life and a potent antagonist activity, effectively ameliorates bleomycin-induced lung fibrosis in mice. In this proposal, there are two specific aims: 1) to determine the effect of PEG-TGF-B peptantagonist on TGF-B-induced fibrogenesis in hepatic stellate cells and myofibroblast-like HSCs. The methodologies will include stellate cell isolation, biochemical and cell biological assays and 2) to evaluate the therapeutic efficacy of PEG-TGF-B peptantagonist in HF using animal models. The methodologies will include biochemical, molecular biological, quantitative histopathological and immunohistochemical analyses. We believe that PEG-TGF-B peptantagonist should be an ideal drug candidate for treating HF in humans.
The goal of this project is to develop a novel therapeutic agent for HF for which effective treatments do not exist at present. The novel TGF-B receptor antagonist developed in this project should be an ideal drug candidate for treating HF in humans.
