Hepatic Growth Factor Mimetic for Liver Fibrosis

描述（由申请人提供）：肝纤维化是一种影响全球数千万患者的疾病，是对病毒性乙型或丙型肝炎、过度饮酒、铁超载或肝外梗阻等慢性损伤的肝脏瘢痕反应，可发展为肝硬化、肝功能衰竭和死亡。事实上，由于丙型肝炎流行以及与非酒精性脂肪性肝炎相关的肝脏疾病发病率不断上升，预计未来十年因肝纤维化/肝硬化并发症死亡的人数将增加两倍。目前可用的治疗方法，包括抗病毒药物，在治疗潜在纤维化方面基本上无效，在大多数情况下，肝移植是唯一有效的选择。散点因子（SF），也被称为肝细胞生长因子（HGF），是一种嗜日性生长因子，主要通过其有丝分裂、运动和形态发生活性诱导多种细胞类型的激活和增殖。此外，SF/HGF通过调节胶原蛋白和转化生长因子- β等关键促纤维化因子发挥抗纤维化作用。事实上，最近发表的几项研究已经证明了外源性给药SF/HGF在肾、肺和肝纤维化动物模型中的治疗潜力。在Angion中发现了一种SF/HGF的小分子模拟物，它概括了体外和体内SF/HGF的所有活性，并在两种动物模型中显示出对肝纤维化的保护作用。为了进一步开发这一有前景的化合物作为纤维化性肝病的潜在治疗药物，我们将在三种动物模型上对其在肝纤维化中的疗效进行评估，包括剂量、治疗时间和给药途径，药代动力学、毒理学和遗传毒性研究，蛋白质组学研究其作用机制。这些研究旨在为IND申请的提交收集完整的数据集。一种安全有效的抗纤维化药物有望减缓或阻止肝纤维化的进展，预防终末期肝硬化的发展，并可能逆转疾病的病理过程。

DESCRIPTION (provided by applicant): Hepatic fibrosis, a disease affecting tens of millions of patients worldwide, is the liver scarring response to chronic injury from viral hepatitis B or C, excessive alcohol use, iron overload or extrahepatic obstructions and can progress to liver cirrhosis, liver failure and death. In fact, deaths from complications of liver fibrosis/cirrhosis are expected to triple over the next decade as a result of the hepatitis C epidemic and the growing incidence of liver disease associated with non-alcoholic steatohepatitis. Currently available therapies, including antiviral, are largely ineffective in treating the underlying fibrosis, and in the majority of cases, liver transplantation is the only effective option. Scatter factor (SF), also known as hepatocyte growth factor (HGF), is a apheliotropic growth factor that induces the activation and proliferation of diverse cell types, largely through its mitogenic, motogenic and morphogenic activities. Additionally, SF/HGF exerts antifibrotic effects by modulating key profibrogenic elements including collagen and transforming growth factor-beta. In fact, several recently published studies have documented the therapeutic potential of exogenously administered SF/HGF in animal models of renal, pulmonary and liver fibrosis. A small molecule mimetic of SF/HGF has been discovered at Angion that recapitulates all in vitro and in vivo SF/HGF activities and has been shown to protect against liver fibrosis in two animal models. In order to further develop this promising compound as a potential therapeutic for fibrotic liver disease, it will be evaluated (1) in three animal models for its efficacy in liver fibrosis with respect to dose, time course of treatment, and route of administration, (2) in the studies of pharmacokinetics, toxicology and genotoxicity, (3) in the studies on its mechanism of action by proteomics. These studies are designed to collect complete data sets for the filing of an IND application. A safe and effective antifibrotic agent is expect to slow or stop the progression of liver fibrosis, prevent the development of end-stage liver cirrhosis, and possible reverse the pathological course of the diseases.