Genetically engineered pig-to-human liver xenotransplantation

Abstract

Background & aims: The advent of genetically edited pig-to-human xenotransplantation has predominantly focused on cardiac and renal applications, with no reported cases of pig-to-human liver xenotransplantation. This study presents the world's first successful genetically modified pig auxiliary liver xenotransplantation in a living human, achieving unprecedented survival of 171 days, and provides valuable insights into the critical factors influencing the procedure's success.

Methods: A genetically modified pig liver, incorporating 10 targeted gene edits, was transplanted as an auxiliary organ into a patient with large hepatocellular carcinoma in the right hepatic lobe, which was initially deemed ineligible for curative resection. Liver function, metabolic, and coagulation markers were closely monitored throughout the perioperative period.

Results: For the first 31 days post-transplant, no hyperacute or acute rejection, infections, or significant complications were observed, and the patient's hepatic and renal function remained stable. Early postoperative coagulopathy, as indicated by elevated D-dimer and fibrin degradation products, was successfully managed through anticoagulant therapy. However, on postoperative day 38, the auxiliary liver was removed due to xenotransplantation-associated thrombotic microangiopathy (xTMA). Subsequent management with eculizumab and plasma exchange successfully resolved the xTMA. Unfortunately, repeated upper gastrointestinal hemorrhage ultimately led to the patient's death on day 171.

Conclusions: This study demonstrates the feasibility of auxiliary porcine liver xenotransplantation as a bridging approach to human liver transplantation. Postoperative xTMA presents a significant challenge to long-term success, highlighting the need for further research to improve xenotransplantation outcomes.

Impact and implications: This study reports the world's first auxiliary xenotransplantation from a 10-gene-edited pig to a living human recipient - distinct from previous studies involving brain-dead recipients. The donor liver was engineered using a 10-gene editing platform, including the knockout of xenoantigen genes and the knock-in of seven human transgenes for immune and coagulation compatibility - pushing the boundaries of synthetic biology in clinical transplantation. The porcine graft exhibited metabolically active liver function, bile secretion, and coagulation correction, demonstrating not only survival but clinically meaningful function. Our work documents, for the first time, xenotransplantation-associated thrombotic microangiopathy in a living human recipient, with comprehensive immunological and histopathological analysis - critical knowledge for the field.

Keywords: Gene editing; Liver xenotransplantation; Pig-to-human; Thrombotic microangiopathy.