Additive and Protective Strategies in an Experimental DCD Porcine Model of Ex vivo
Synopsis: Remarkable progress has occurred in the development of portable technologies to support ex vivo normothermic liver perfusion (EVNLP). Clinical trials have been initiated, and preliminary outcomes suggest potent protection of marginal liver grafts. These findings will have huge bearing in expanding the limited liver donor pool, and will save lives where up to 1:5 die waiting on lists.
We have developed a stable DCD donor model of liver transplantation in the pig using EVNLP, modeled closely to the OrganOx Metra system that we are currently piloting in pilot clinical trial in Edmonton. Based on our extensive previous work of cellular protection in experimental and clinical islet transplantation, we herein propose to explore the potential of a series of potent anti-inflammatory and pan-caspase cytoprotective strategies. We hypothesize that the rational addition of selective protectant compounds to the ex vivo
circuit will improve the safe transplantation of more marginal DCD liver grafts. Furthermore, administration within the ex vivo
circuit will circumvent early hurdles commonly associated with early phase clinical trial testing, as the liver graft will be treated rather than the recipient. The compounds that have demonstrated strong potency in our laboratory include 1) pan-caspase inhibitors 2) inhibitors of regulated necrosis and 3) anti-freeze glycoproteins, all of which would serve well in additive strategies.
We are excited about the potential combination of these cytoprotective additives to
EVNLP, and are confident that this work will yield translatable findings that will have
major impact in the future practice of clinical liver transplantation.