Amir Sanatkar ^* Kohei Kinoshita Akihiro Maenaka David K. Cooper

• Center for Transplantation Sciences, Transplant Center, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Charlestown, United States

An overview is provided of the evolution of strategies towards xenotransplantation during the past almost 40 years, focusing on advances in geneediting of the organ-source pigs, pre-transplant treatment of the recipient, immunosuppressive protocols, and adjunctive therapy. Despite initial challenges, including hyperacute rejection resulting from natural (preformed) antibody binding and complement activation, significant progress has been made through gene editing of the organ-source pigs and refinement of immunosuppressive regimens. Major steps were the identification and deletion of expression of the three known glycan xenoantigens on pig vascular endothelial cells, the transgenic expression of human 'protective' proteins, e.g., complement-regulatory, coagulation-regulatory, and anti-inflammatory proteins, and the administration of an immunosuppressive regimen based on blockade of the CD40/CD154 T cell co-stimulation pathway. Efforts to address systemic inflammation followed. The synergy between gene editing and judicious immunomodulation appears to largely prevent graft rejection and is associated with a relatively good safety profile. though there remains an incidence of severe or persistent proteinuria (nephrotic syndrome) in a minority of cases. This progress offers renewed hope for patients in need of life-saving organ transplants.