Hepatocyte 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，是对病毒性肝炎B或C、过量饮酒和铁超负荷造成的慢性损伤的反应，通常导致肝功能衰竭和死亡。尽管有抗病毒和其他治疗方法，但大多数在治疗潜在的纤维化方面无效，并伴有许多副作用。由于丙型肝炎（HCV）的流行和与肥胖相关的肝病（所谓的“非酒精性脂肪性肝炎”（NASH））的发病率不断增加，预计未来十年肝纤维化并发症的死亡率将增加两倍。越来越多的患者需要到三级护理中心进行肝移植。不幸的是，可供移植的尸体器官数量已经趋于稳定，活体亲属捐献者移植并没有缩短等待名单。因此，迫切需要有效的抗纤维化疗法。最近发表的几项研究已经证明了外源性HGF在治疗肝纤维化动物模型中的治疗潜力。内源性HGF至少部分通过下调TGF β 1（纤维形成的最有效因子）在抑制纤维形成中起关键作用。它还可以通过其增殖和抗凋亡作用起作用。 虽然HGF的施用有望作为治疗肝纤维化的治疗途径，但众所周知，基于蛋白质的疗法难以施用，因为潜在的免疫应答、溶液的不稳定性和成本高昂的生产方案。为了克服这些不足，模拟HGF活性的低分子量化合物将提供显著改善的治疗潜力。Angion Biomedica Corp.已经鉴定出C6，一种在体外和体内都能模拟HGF作用的小分子量化合物。C6抑制肾细胞凋亡，促进血管生成，防止肾缺血引起的肌酐增加，并降低肾衰竭氯化汞模型中肾小管坏死的发生率。C6可能在肝纤维化动物模型中具有抗纤维化作用。这些研究将为更广泛的II期研究提供基础，以将这种潜在的疗法带入临床试验。

DESCRIPTION (provided by applicant): Hepatic fibrosis, a disease affecting tens of millions of patients worldwide, is the liver scarring response that occurs in response to chronic injury from viral hepatitis B or C, excessive alcohol use, and iron overload, and often leads to liver failure and death. Despite the availability of antiviral and other therapies, most are ineffective in treating the underlying fibrosis and are associated with many side effects. Death from complications of liver fibrosis is expected to triple over the next decade as a result of the hepatitis C (HCV) epidemic and growing incidence of liver disease associated with obesity, so-called "non-alcoholic steatohepatitis" (NASH). Increasing numbers of patients are presenting to tertiary care centers in need of liver transplantation. Unfortunately, the number of cadaveric organs available for transplantation has plateaued and living related donor transplants have not shortened waiting lists. Hence, there is a critical need for potent antifibrotic therapies. Several recently published studies have demonstrated the therapeutic potential of exogenously administered HGF in the treatment of animal models of liver fibrosis. Endogenous HGF plays a key role in inhibiting fibrogenesis at least in part by downregulating TGFb1, the most potent factor for fibrogenesis. It may also act by its proliferative and anti-apoptotic actions. While administration of HGF holds promise as a therapeutic avenue for the treatment of liver fibrosis, protein-based therapies are notoriously difficult to administer because of potential immune responses, instability in solution, and cost-prohibitive production schemes. To overcome these shortfalls, low molecular weight compounds that mimic the activity of HGF would provide substantially improved therapeutic potential. Angion Biomedica Corp. has identified C6, a small molecular weight compound that mimics the effects of HGF both in vitro and in vivo. C6 inhibits renal cell apoptosis, promotes angiogenesis, prevents increased creatinine by renal ischemia and decreases the incidence of tubular necrosis in the mercuric chloride model of kidney failure. It is likely that C6 will have an antifibrotic effect in an animal model of liver fibrosis. These studies will provide the basis for more extensive Phase II studies to bring this potential therapy into clinical trials.