A Novel TGF-β Receptor Antagonist to Treat Pulmonary Fibrosis

DESCRIPTION provided by applicant Pulmonary fibrosis PF including idiopathic PF IPF is a group of progressive incurable lung diseases with high mortality rates PF is characterized by excessive deposition of extracellular matrix proteins in lung parenchyma via TGF dependent pathways Existing therapies only modestly slow the progression and likely only indirectly impact TGF mediated pathways Recent identification of the involvement of abnormal lymphangiogenesis in IPF and bleomycin induced PF has provided new insights into cellular and molecular mechanisms that may limit systemic therapeutics It is hypothesized that vascular remodeling which occurs after lung injury leads to deposition of hyaluronic acid a component of lymph and a weak lymphangiogenesis factor This results in abnormal lymphangiogenesis which produces new lymphatic vessels with functional defects lymphatic drainage defects leading to the vicious cycle of repeated injury and fibrosis Abnormal lymphangiogenesis a rate limiting step in PF offers an excellent target for future inhaled PF therapeutics The molecular basis of the role of abnormal lymphangiogenesis in the formation of PF is unknown We hypothesize that TGF a potent fibrogenic cytokine produced in lung upon injury contributes to abnormal lymphangiogenesis which occurs during vascular remodeling after lung injury and is involved in the vicious cycle of repeated injury and fibrosis injury abnormal lymphangiogenesis lymphatic drainage defects accumulation of TGF n which leads to PF This hypothesis is based on several lines of evidence TGF accumulates in lung tissues of PF including IPF TGF inhibits normal lymphangiogenesis in lung tissues TGF induces lung edema by increasing epithelial and endothelial permeability and TGF is a major cytokine which is responsible for production of fibrotic extracellular matrix This hypothesis suggests that to ameliorate PF TGF antagonists targeted to the lung draining lymphatic systems by intrapulmonary administration can inhibit not only the matrix production but the cycle of repeated injury and fibrosis In the last decade TGF binding proteins anti TGF antibodies and soluble type II TGF receptors and small molecule inhibitors which target latent TGF activation and TGF signaling have been developed and used to treat PF in animal models However the lung draining lymphatics are not specifically targeted in these treatments This will limit their efficacy in treating human patients In additio these agents have systemic and off target effects that result in narrow therapeutic windows To address the limited efficacy and off target effects we generated a novel TGF receptor antagonist with both TGF antagonist and wound healing promoting activities It can be effectively safely and affordably used for the management of PF in humans In this project we will determine the efficacy of this antagonist in treating PF by intranasal delivery which targets the lung lymphatic system and lung parenchyma in two mouse models of lung fibrotic disease We expect that the results from these proposed studies will lead to a novel effective therapy of PF in patients PUBLIC HEALTH RELEVANCE The goal of this project is to develop a novel TGF receptor antagonist which exhibits anti fibrotic and wound healing activities as a drug candidate It is expected to ameliorate and reverse lung fibrosis which currently lacks effective therapy The clinical availability of this novel and potent antagonist will benefit millions of patients worldwie