Surgeon-scientists from the University of Maryland School of Medicine have published new research in Nature Medicine and Nature detailing insights from genetically engineered pig heart transplants into both non-human primates and humans, offering both promise and highlighting challenges in the field of xenotransplantation. The work emphasizes the potential to address the critical shortage of donor organs, while also underscoring the complex immunological hurdles that remain.
Xenotransplantation in Non-Human Primates
Researchers transplanted 10-gene-edited (10-GE) pig hearts into baboons, achieving survival times up to 225 days. The 10-GE pig hearts included the deletion of four genes (GGTA1, B4GALNT2, CMAH, and GHR) and the overexpression of six human genes (hCD46, hDAF, hTBM, hEPCR, CD47, and HO-1). The study used a costimulation-based immunosuppression regimen, including anti-CD20 antibody, ATG, C1 Esterase Inhibitor, and primatized anti-CD40.
"This study demonstrates long-term cardiac xenotransplant survival from 10 GE donor pigs into baboons but also highlights the detrimental effect of CMAHKO on NHP models," the authors noted in Nature. They also found that the survival was less than previously reported using 7-GE xenografts but longer than reported using 9-GE xenografts. The team also retrospectively tested 10-GE cardiac xenografts and found that three out of four cardiac xenografts were positive for PCMV, and their xenograft survivals were 225, 127, and 55 days.
The research indicated that the knockout of the CMAH gene, which encodes N-glycolylneuraminic acid (Neu5Gc), may have contributed to shorter survival in non-human primates. Baboons, unlike humans, possess a functional CMAH gene and, therefore, do not have antibodies against Neu5Gc. The exposure to an inactive CMAH reveals new epitopes, presenting new targets for antibody binding.
Clinical Insights from Human Xenotransplantation
In a separate report in Nature Medicine, insights were shared from the second patient to receive a genetically modified pig heart. Lawrence Faucette, 58, received a 10-gene-edited pig heart at the University of Maryland Medical Center in 2023. He survived for 40 days before the transplant began to fail due to rejection. The paper documents initial signs of rejection of the 10 gene-edited pig heart on the first biopsy performed about two weeks after the surgery.
Bartley P. Griffith, MD, who surgically transplanted the pig heart, stated, "We have taken another important step forward in the quest to address the global shortage of donor hearts, and we once again found that the porcine heart demonstrated excellent systolic and diastolic function during the initial weeks post-transplantation."
The study identified a surge in pre-existing anti-pig antibodies, leading to damage and graft failure, despite selecting a patient with low initial antibody levels. Muhammad M. Mohiuddin, MD, noted, "Their sacrifice yielded crucial scientific insights into how we and others should proceed to learn how to prevent graft failure from happening in future transplants."
Implications for Future Xenotransplantation
These studies underscore the potential of multi-gene edited donor organs to overcome hyperacute and acute xenograft rejection. However, they also highlight the need for continued research into immunosuppression strategies and the role of specific gene edits, such as CMAH knockout, in different recipient populations. The research suggests that 10-GE xenografts might be more suitable for clinical xenotransplantation than in NHPs.
Mark T. Gladwin, MD, Dean of UMSOM, stated, "Our physician-scientists continue to work towards a better understanding of how to prevent porcine organ rejection despite aggressive immunosuppression and early successful surgical and hemodynamic outcomes."
