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.
