National I-Corps: Development of synthetic heparin to protect liver graft from ischemia reperfusion injury during transplantation

Project Summary/Abstract According to the most recent data published by the Global Cancer Observatory, over 900,000 patients worldwide were diagnosed with liver cancer in 2020. For patients with hepatocellular carcinoma, the most common type of liver cancer, liver transplantation is the only potentially curative treatment option. Liver transplantation inevitably involves periods of time where the liver is removed from blood circulation during procurement. When the liver is connected to the recipient and blood flow is restored, the ischemia phase damage causes inflammation and coagulation complications. This ischemia reperfusion (IRinj)ury is a key factor in morbidity and mortality after transplantation. Furthermore, there is preclinical and clinical evidence that IR injury leads to cancer recurrence in over 20% of patients within 3 years. Despite these poor outcomes, there are no approved therapeutics available targeting IR injury during liver transplantation. Potential therapeutics could improve post-transplant organ function and reduce the risk of cancer recurrence. This phase I STTR is focused on developing a therapeutic strategy to decrease IR injury during liver transplantation. We have identified a novel synthetic oligosaccharide structure called dekaparin, produced exclusively by Glycan Therapeutics, with a dual mechanism of action. IR injury leads to a hypercoagulable state with a flux of immune mediators, primarily neutrophils, infiltrating reperfused tissue resulting in tissue damage. Dekaparin has anticoagulant and anti-inflammatory activity and is effective in reducing warm IR- mediated liver injury in a mouse model that mimics surgical complication. The necessity of dual activity was demonstrated using other oligosaccharides that have only anticoagulant or anti- inflammatory activity. Single activity oligosaccharides decreased liver injury when combined but not when used separately. In this current application, we propose to evaluate dekaparin’s therapeutic potential against ischemia injury happening during graft procurement and preservation using an ex vivo model of rat liver perfusion after cold storage. Five tasks are planned to support this single aim: 1) Complete 10 g synthesis of dekaparin for ex vivo studies; 2) Establish ex vivo model of isolated perfused rat liver; 3) Evaluate effect of dekaparin on IR injury in ex vivo model; 4) Use extended criteria liver grafts in ex vivo model with dekaparin; 5) Purify dekaparin from spent perfusate to recycle material for future use. In Phase II, we will use the ex vivo model to explore different doses of dekaparin. We will conduct the in vivo orthotopic liver transplantation model in rats. Lastly, we will evaluate the metastatic ability of circulating tumor cells in the transplant model with dekaparin treatment to determine tumor recurrence potential.