Development of synthetic heparin to protect liver graft from ischemia reperfusion injury during transplantation

Project Summary/Abstract This STTR phase II application is to seek continuation support to develop a carbohydrate-based reagent, dekaparin, to protect from liver damage during the organ recovery and preservation process. Liver transplant is an effective treatment option for hepatocellular carcinoma and end stage liver disease patients. However, the transplant process unavoidably involves ischemia- reperfusion (IR) injury. IR injury leads to adverse outcomes in recipients including primary non- function of the graft, biliary complications, acute cellular rejection and tumor recurrence. Furthermore, due to the high demand of limited available organs, extended criteria donor (ECD) livers, which are more susceptible to IR injury, are often allocated to liver tumor patients who have preserved liver function. Retrospective studies have found that over 20% of recipients receiving ECD grafts have tumor recurrence within 3 years post-transplant. Currently, there are no preservation solutions equipped to decrease IR injury beyond what is experienced by ideal donors after a short cold storage time. Therefore, targeting IR injury to prevent adverse post-transplant outcomes is of urgent importance. Considering the multiple mechanisms of action of dekaparin, we expect that adding dekaparin to preservation solutions will reduce IR injury in the recipient, translating to a reduction in early allograft dysfunction, improved graft survival and fewer re- transplants needed. The overall goal of this work is to increase the utilization of ECD livers by reducing the IR injury burden that is often associated with ECD use. In this way, more recipients can receive a life-saving liver transplant. In the Phase I project period, dekaparin was used in an ex vivo model of liver perfusion and demonstrated efficacy in reducing liver injury after cardiac arrest and cold ischemia. Additionally, during the Phase I project period, our team participated in NIH National I-CORPS to validate our beachhead market as an additive in organ preservation solution. In this Phase II proposal, four specific aims are proposed to complete preclinical studies and prepare for a pre-submission meeting request by the end of the project period. The specific aims include 1) evaluating dekaparin’s effect against IR injury in a deceased donor porcine liver transplantation model; 2) evaluating dekaparin’s effect on tumor recurrence after deceased donor rat liver transplantation; 3) dekaparin use in an ex vivo human discarded liver model with machine perfusion; and 4) determination of dekaparin concentration in biological samples from Aims 1-3. We intend to apply for a STTR Phase IIb award with matching funding from a strategic partner to complete an early feasibility, first in human study.