Hepatocyte Growth Factor Mimetic for Liver Fibrosis

描述(申请人提供)：肝纤维化是一种影响全球数千万患者的疾病，是由于乙型或丙型病毒性肝炎、过量饮酒和铁负荷造成的慢性损伤而产生的肝脏疤痕反应，通常会导致肝功能衰竭和死亡。尽管有抗病毒和其他疗法可用，但大多数在治疗潜在的纤维化方面无效，并与许多副作用有关。由于丙型肝炎(丙型肝炎)的流行和与肥胖相关的肝病的发病率不断上升，即所谓的非酒精性脂肪性肝炎(NASH)，预计未来十年死于肝纤维化并发症的人数将增加两倍。越来越多的需要肝移植的患者被送往三级护理中心。不幸的是，可供移植的身体器官数量已经停滞不前，活体亲属捐赠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表明，外源性给予HGF在治疗肝纤维化动物模型中具有治疗潜力。内源性HGF在抑制纤维化形成中起关键作用，至少部分是通过下调TGFb1，TGFb1是最有效的纤维化形成因素。它还可能通过其增殖和抗凋亡作用发挥作用。 虽然给予HGF有望成为治疗肝纤维化的一种途径，但众所周知，基于蛋白质的疗法很难实施，因为潜在的免疫反应、溶液的不稳定以及成本高昂的生产方案。为了克服这些不足，模仿HGF活性的低分子化合物将提供显著改善的治疗潜力。Angion Biomedica Corp.已经确定了C6，这是一种小分子化合物，在体外和体内都能模仿HGF的作用。在氯化汞肾功能衰竭模型中，C6抑制肾细胞凋亡，促进血管生成，防止肾缺血引起的肌酐升高，并降低肾小管坏死的发生率。在肝纤维化的动物模型中，C6很可能具有抗纤维化作用。这些研究将为更广泛的第二阶段研究提供基础，以便将这种潜在的治疗方法带入临床试验。

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.