Refanalin for Liver Transplantation

描述(由申请人提供)： 原位肝移植是治疗终末期肝病的最有效方法。与取回、储存和移植肝脏相关的缺血再灌注损伤是影响早期移植物功能和限制移植物长期存活的一个主要的免疫非依赖性因素。边缘供者的肝脏，包括脂肪变性的肝脏，更容易受到缺血再灌注损伤的影响，经常无法移植。分散因子/肝细胞生长因子是一种具有显著保肝活性的肝营养因子。然而，它的临床应用受到与其给药相关的后勤困难的限制。 我们已经鉴定出Refanalyin，一种有机小分子分散因子/肝细胞生长因子模拟物，具有显著的细胞保护活性。在器官特异性缺血损伤的动物模型中，Refanalyin可以缩小梗塞面积并改善功能。在体全肝缺血再灌注模型中，瑞法林可减轻肝脏损伤，减轻肝细胞凋亡和坏死，保护肝脏超微结构。目前的第二阶段方案探讨了瑞法林在临床相关的原位肝移植模型中的治疗潜力。通过减轻同种异体移植物功能障碍和预防同种异体移植失败，瑞法林可以降低受体的发病率和死亡率。通过减轻边缘肝脏的缺血再灌注损伤，Refanalyin可以挽救原本被丢弃的器官，并增加捐赠者的储备。

DESCRIPTION (provided by applicant): Orthotopic liver transplantation is the most effective treatment for patients with end-stage liver disease. Ischemia-reperfusion injury associated with the retrieval, storage and transplantation of livers is a major immune-independent factor adversely affecting early graft function, and limiting long-term graft survival. Marginal donors livers, including steatotic livers, are even more susceptible to ischemia-reperfusion injury, and often fail transplantation. Scatter factor/hepatoyte growth factor is a hepatotrophic factor with significant hepatoprotective activity. However its clinical use is limited by the logistical difficulties associated with its administration. We have identified Refanalin, an organic small molecule scatter factor/hepatocyte growth factor mimetic, with significant cytoprotective activity. In animal models of organ-specific ischemic injury, Refanalin attenuates infarct size and improves function. In in vivo global hepatic ischemia-reperfusion, Refanalin reduces hepatic injury, attenuates hepatocyte apoptosis and necrosis and preserves hepatic ultrastructure. The present Phase II proposal explores the therapeutic potential of Refanalin in clinically relevant models of orthotopic liver transplant. By attenuating allograft dysfunction and preventing allograft failure, Refanalin can reduce recipient morbidity and mortality. By attenuating ischemia-reperfusion injury in the marginal liver, Refanalin can salvage an otherwise discarded organ, and increase the donor pool.