Xenotransplantation: The Present Future

Early this year, news broke that the first xenotransplant of a genetically engineered pig heart into a human had been successfully performed at the University of Maryland Medical Center. Pictures, videos and stories of the recipient, the surgical team and the research behind this milestone were shown across various news outlets and social media. Unfortunately, despite an initially well-functioning heart post-transplant, the recipient died after two months.

The last time xenotransplantation received so much worldwide attention would have to be more than 35 years ago, when Stephanie Fae Beauclair (then known as Baby Fae) received a xenotransplant of a baboon heart and survived for 21 days before ultimately dying due to rejection of the heart by her immune system.

While these two stories may sound similar, their implications are drastically different. Due to ethical concerns, logistical issues and the infectious potential of using nonhuman primates as donors, xenotransplantation has shifted to using pigs. Pigs are more genetically distant (100 million years in evolutionary distance) and thus more different from humans anatomically, physiologically and immunologically than primates. As a result of these differences, xenotransplantation using pigs is faced with major obstacles: hyperacute rejection (within minutes to hours due to existing antibodies), delayed rejection (within weeks to months), and trans-species infection.

Prior recipients of xenotransplant pig hearts did not survive beyond one week, and most succumbed to hyperacute rejection, the first obstacle to xenotransplantation. Overcoming hyperacute rejection has become feasible with recent advancements in genetic engineering techniques. Specifically, gene-knockout techniques enable the removal of three specific carbohydrates (Galactose-α1,3-galactose or Gal, N-glycolylneuraminic acid or Neu5Gc, and Sd) expressed on the cell membrane in pigs that would otherwise be recognized and targeted by antibodies within the human body.

Delayed rejection is often mediated by complement (part of the immune system that enhances the function and ability of antibodies and other cells) activation and dysfunction in blood clotting. Complement activation, which results from the body recognizing something as “foreign,” is achieved by the production of complement regulatory proteins such as the membrane cofactor protein (CD46) and membrane-attack-complex-inhibitory protein (CD59). With the advent of transgenic technology, these human proteins can now be expressed in pigs by inserting the underlying genes into the pig genome, thereby reducing complement-mediated injury. The donor pig used in this year’s case had 10 genetic modifications, including four inactivations and six such insertions. Research on the optimal immunosuppressive regimen to combat other aspects of delayed rejection are ongoing.

In his recent keynote speech at the American Association for Thoracic Surgery annual meeting, Bartley Griffith, leader of the xenotransplantation program at the University of Maryland and surgeon for this year’s landmark xenotransplantation, discussed the recent finding that porcine cytomegalovirus (CMV) may have played a role in contributing to the recipient’s ultimate demise. Of note, porcine CMV has been previously demonstrated to negatively affect survival in xenotransplantation using pig organs into baboons. As more is learned about such trans-species infection and more prevention strategies are employed, xenotransplantation is expected to become safer. Currently, the pigs used for xenotransplantation are born via C-section and raised under strictly controlled conditions to minimize infection; it is conceivable that such controlled conditions may one day make xenotransplantation safer than allotransplantation, transplant using a human donor.

Norman Shumway, a pioneer in heart transplant, once said that, “Xenotransplantation is the future and always will be.” This year’s landmark xenotransplantation is evidence that this is feasible at the present. As we look forward to the future, xenotransplantation may be just around the corner.

References:

  1. Chaban, R, Cooper, DK, and Pierson, RN. “Pig heart and lung xenotransplantation: Present status.” The Journal of Heart and Lung Transplantation. In Press; May 2022
  2. Denner, J, Langin, M, Reichart, B, et al. “Impact of porcine cytomegalovirus on long-term orthotopic cardiac xenotransplant survival.” Scientific Reports. 10: 17531; Oct 2020
  3. Farr, M and Stehlik, J. “Heart xenotransplant: a door that is finally opening.” Circulation. 145: 871 – 873; Jan 2022
  4. Fischer, K and Schnieke, A. “Xenotransplantation becoming reality.” Transgenic Research. 31: 391-398; May 2022
  5. Kidder, L. “Stephanie’s Heart: The Story of Baby Fae.” Loma Linda University Health. Sept 8, 2016
  6. Mohiuddin, MM, Reichart B, Byrne GW, et al. “Current status of pig heart xenotransplantation.” International Journal of Surgery. 23: 234 – 239; Nov 2015
  7. Pierson, RN, Fishman, JA, Lewis, GD, et al. “Progress toward cardiac xenotransplantation.” Circulation. 142:1389–1398; Oct 2020
  8. Rabin RC. In a first, man receives a heart from a genetically altered pig. The New York Times. Jan 10, 2022
  9. Reardon, S. “First pig-to-human heart transplant: what can scientists learn?” 601: 305-306; Jan 2022
  10. Shu, S, Ren J, and Song J. “Cardiac xenotransplantation: a promising way to treat advanced heart failure.” Heart Failure Reviews. 26: 1527; Nov 2021

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