Clinically Relevant Pharmacologic and Immunomodulatory Strategies to Achieve Long-term Survival of Kidney Xenografts in Primates

Xenotransplantation (XTx) represents a possible solution to the organ shortage crisis and is an imminent clinical reality with long-term xenograft survival in pig-to-nonhuman primate (NHP) heart and kidney large animal models, and short-term success in recent human decedent and clinical studies. We have recently reported consistent >8 months survival in consecutive cases of pig-to-baboon kidney xenotransplantation (KXTx) using source pigs with 10 genetic modifications. These data provide critical supporting evidence for the safety and feasibility of clinical kidney xenotransplantation (KXTx) and resulted in FDA clearance of the first-ever human clinical trial of a xenoorgan. However, these studies also identified new challenges that will need to be addressed to ensure safe clinical translation of preclinical data in xenotransplantation. The overall goal of this project is to address these remaining issues, to elucidate underlying mechanisms of graft loss and injury, and to test novel targeted strategies with the goal of facilitating clinical translation of XTx with consistent and durable graft survival. Accordingly, we have outlined the following specific aims: (1) to optimize a clinically relevant immunosuppression regimen consisting of FDA-approved medications, targeting specific pathways involved in both early and late graft loss, and to characterize the risk of sensitization associated with xenotransplantation; and (2) to evaluate the impact of vascularized thymus co-transplantation on xenograft survival. We will attempt to prolong kidney xenograft survival with FDA-approved immunosuppression by combining innovative strategies: preventing the early graft injury that leads to long-term xenograft dysfunction by targeting evidence-based pathways involved in ischemia reperfusion injury and xeno-specific rejection, using multi-KO and transgenic source pigs, and including the immunomodulatory strategy of vascularized thymic transplantation. If successful, our approach could provide a virtually limitless supply of xenogeneic kidneys for human patients to meet the demands of the organ shortage, and may enable reduction or elimination of lifelong immunosuppression.