Applying Genomics and Omics in Pig to Human Decedent Xenotransplantation - PROJECT SUMMARY – OVERALL Xenotransplantation has the potential to provide nearly unlimited organs for transplantation. Extension of xenograft survival in nonhuman primates (NHP) and xenotransplants to living and brain-dead humans have advanced the field toward clinical trials. Despite these advances, xenograft survival in the few clinical cases performed to date have been limited by infectious complications (of both host and donor origin) and by the development of cellular and antibody-mediated rejection. The development of sensitive assays to detect host and donor microbes, coupled with platforms to guide clinical responses, and assays to detect early markers of xenograft rejection would improve outcomes of clinical xenotransplants. At NYU Langone, we developed an innovative decedent model to study the results of xenografts transplanted to humans and gain experience in a fail-safe environment that also enables frequent sampling of recipient blood and tissues. We have now performed three kidney and two heart xenotransplants in the decedent model, along with one clinical kidney xenotransplant. We have performed innovative multi-omic analyses of the recipients of these transplants. Our preliminary data show that we can detect both host and donor-derived microbes in decedents with an unbiased approach, and that we can detect donor-derived cell-free DNA in recipients at the time of biopsy- proven rejection episodes. We now plan to biobank specimens from 21 additional decedents and perform multi-omic analyses of these recipients. Our program consists of two projects: Project 1 develop sensitive assays to detect host- and donor-derived microbes post-transplant and develop platforms that guide effective clinical management of infections in xenograft recipients; Project 2 will develop assays to detect donor-derived cell-free DNA in recipient blood. We will expand these studies by developing a methylation atlas of pig cells that will enable us to identify the cell of origin of any donor-derived cell-free DNA we detect. The projects will be supported by two Cores: The Molecular Science core contains biobanked specimens from the 5 decedents we have performed to date. We will biobank specimens from the additional 21 decedents and then perform multi-omic analyses of these samples. The Core will also support data analysis of these results. The Administrative Core will provide administrative oversight, coordinate internal scientific meetings, organize travel to consortia meetings, and ensure each Project is meeting their defined milestones. Collectively, these projects will provide a new level of understanding of the management of xenograft recipients and the human immune response to xenografts. Upon successful completion of the proposed research, we expect to develop platforms that improve the clinical management of patients who enroll in the first clinical trials of xenotransplantation, with the long-term goal of developing xenotransplantation into a standard clinical treatment option for organ failure.
