Scleroderma (also known as systemic sclerosis-SSc) is an autoimmune disorder characterized primarily by progressive dermal and vascular fibrosis. Other organs are affected too, including lung, heart, esophagus, intestine, and kidney. Many patients who suffer from scleroderma/SSc also have a loss of pulmonary function. Scleroderma/SSc affects approximately 400,000 to 900,000 people in the United States every year. Mortality and morbidity in SSc are very high and are directly related to the extent of fibrosis in the involved organs. According to one study, the total cost attributed to scleroderma/SSc in the United States reached $1.5 billion annually. In this study, morbidity represented the major cost burden, associated with $820 million (56%) of the total costs. There is no known cure for scleroderma/SSc and the underlying cause remains unknown, though it is attributed to having an autoimmune component. Treatment is currently limited to management of symptoms in order to improve quality of life and limit long-term complications. Common treatments for scleroderma/SSc include immunosuppressive agents, anti-inflammatory agents, vasodilators and anti-fibrotic agents. Immunosuppressive agents such as corticosteroids and cyclophosphamide have demonstrated marginal efficacy, or have side effects. Therefore there is a critical need for effective and affordable therapeutic strategy. Increased expression of both platelet derived growth factor (PDGF) and its receptors (PDGFR1 and PDGFR2) have been demonstrated in skin of scleroderma patients. Furthermore, the possibility of PDGFR activation through auto-antibodies is a novel and provocative concept in autoimmune fibrotic diseases. Recent studies have indicated that another growth factor, vascular endothelial growth factor (VEGF), a potent angiogenic molecule, is over expressed in SSc patients. From an extensive review of the literature, we concluded that inhibiting both PDGFR and KDR (VEGFRII) may be an effective novel therapeutic strategy to benefit scleroderma/SSc patients. We identified a small molecule receptor tyrosine kinase inhibitor with activity against both PDGFR and KDR. We have characterized this molecule in vitro and in vivo and found that ANG-3154 displays significant inhibitory activity in animal models of scleroderma/SSc and lung fibrosis. Given these preliminary studies in combination with the potential clinical advantages of small molecule PDGFR/KDR inhibitors in the setting of scleroderma/SSc, the current SBIR Phase I application is designed to further characterize ANG-3154 in two preclinical animal models of scleroderma/SSc. PUBLIC HEALTH RELEVANCE: Scleroderma also known as systemic sclerosis (SSc) is a disease caused by a surplus of extracellular matrix protein localized in the skin, or it may become systemic with excess collagen collecting in the kidneys, lungs, gastrointestinal tract, and heart. Scleroderma affects approximately 400,000 to 990,000 people in the US every year. Mortality and morbidity in scleroderma/SSc are very high and are directly related to the extent of fibrosis in the involved organs. The exact cause remains unknown even though it is thought to be autoimmune disease and there is no known cure for scleroderma/SSc. The objective of this application is to evaluate a lead small- molecule drug candidate in two preclinical models of scleroderma/SSc to advance to SBIR Phase-II project with the ultimate objective of bringing our drug to clinical trials.
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