Stabilization of gap/tight junctions to ameliorate brain death induced endothelial cell injury

DESCRIPTION provided by applicant Transplantation is a widely accepted and highly successful therapy for end stage heart disease While success rates and survival have risen steadily since its inception almost years ago due largely to improved immunosuppression regimes there is a growing appreciate that factors associated with brain death organ donation procurement and storage prior to implantation greatly effect outcomes post transplantation Clinical data has demonstrated that recipients of hearts from living donors have significantly improved outcomes as compared to those from cadaveric sources These data suggest that insults to the donor organ induced by brain death and cold storage predispose to poorer post transplantation outcomes These injurious events are thought to initiate organ injury endothelial dysfunction and inflammation that are further exacerbated upon implantation and reperfusion and that primes the donor organ for alloimmune recognition Therefore strategies to minimize or switch off these injurious events are likely to improve graft outcomes Cold preservation has greatly facilitated the use of cadaveric hearts for transplantation but clearly damage occurs prior to storage from brain death and during both the preservation episode and the reperfusion phase While metabolic additives have been incorporated into preservation solutions to prolong storage times and improve organ viability no additives have been incorporated into the preservation solutions to minimize endothelial injury activation We hypothesize that brain death cold preservation and ischemia reperfusion injury induces cell junction damage which leads to inflammation heart damage and endothelial dysfunction upon reperfusion and that inclusion of a novel gap and tight junction stabilizing peptide ACT would preserve cell junctions during cold preservation and reduce graft damage and immunogenicity upon reperfusion PUBLIC HEALTH RELEVANCE The greatest rate limiting step to successful transplantation is the shortage of suitable organs for transplant Many candidate hearts are deemed unusable due to brain death induced injury BDI and hearts that are transplanted are often sub optimal due to endothelial activation and injury which promotes primary graft failure Here we explore ACT as a pharmacotherapy to minimize endothelial injury and improve post transplant outcomes