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An Era of Possibilities: A Look into Xenotransplantation

Surgeon team operating.

Within every generation, there is a paradigm shift that has the potential to echo through all specialties of medicine. In early January 2021, Dr. Bartley Griffith and his team performed a landmark surgery, transplanting a pig heart into a human.1 The pig heart, which had 10 genetic modifications, lasted two months in the human recipient.2-4 This surgery was the culmination of breakthroughs in immunology, surgery and genetics, catching people’s attention across the nation.

This transplant methodology, titled xenotransplantation, is the transplant of animal organs and tissues into a recipient of a different species. While there have been prior attempts at xenotransplantation to mitigate the global deficit in organ donations, the majority were rejected immediately. In the search for universal donors, genetic modification has been a pursuit in the field of transplant.5, 6 More recently, an article published in Nature highlighted a monkey who survived for two years with a donor pig kidney that was genetically altered for transplantation.5, 7 This is one of the longest survival times in the history of xenotransplantation. This donor pig organ contained 69 edited genes that played a role in preventing rejection, organ viability, and embedded pig genes (genes that can infect human cells and cause damage) that could cause increased morbidity.5 This was followed by NYU Langone Health transplanting a donor pig kidney into a human who was brain dead, which  lasted for about two months.8 This pig, called the GalSafe pig, was a commercially bred and genetically altered pig from Revivicor Inc. (United Therapeutics Corporation). At the same time, University of Maryland Medical Center was attempting their second pig heart transplant in Lawrence Faucette, who died six weeks post-transplant.9 All of these efforts are attempts to address the worldwide shortage of organs.

Currently, we immunosuppress recipients of transplants to prevent their cells from rejecting and attacking the transplant. If we continue using human tissue, we will continue to have disproportionate rejections and expose patients to potent immunosuppressants for a chance at success. However, advances in gene editing using a system called CRISPR-Cas9 allow modifications to animal genomes that can decrease the likelihood of organ rejection.6, 10 The recent tentative success of the CRISPR-edited pig heart and kidney xenotransplantation is a paradigm shift that could apply to all organ xenotransplantation.1, 5, 11, 12 Not only could genetically modified organs decrease the worldwide deficit of organ donations, but they could also decrease the transplant rejection rate without exposing patients to potent systemic pharmaceuticals.

As an ophthalmologist in training, I was particularly interested in this discovery due to its impact on corneal transplants. Currently, only one cornea is available for every 70 needed for transplantation, leaving a deficit affecting 12.7 million people worldwide.13-15 While those in the United States have better access to corneal transplantation, the proportion of domestic patients who experience immunologic rejection still ranges from 18% to 21%.13 Gene editing of organs and tissues is a novel technology, and its use in corneal transplant will require specific research and trials, just as other xenotransplanted organs.

While this appears to be a new horizon for the future of transplantation, additional research and medical steps will need to be taken before this type of method is utilized in medical practice. The FDA has signaled they are willing to discuss and monitor these continued attempts at xenotransplantation.16 Overall, xenotransplantation has opened the door to the possibility of universal donors for previously scarce interventions, leaving an open ending to the evolving story of xenotransplantation.

  1. Griffith BP, Goerlich CE, Singh AK, Rothblatt M, Lau CL, Shah A, Lorber M, Grazioli A, Saharia KK, Hong SN, Joseph SM, Ayares D, Mohiuddin MM. Genetically Modified Porcine-to-Human Cardiac Xenotransplantation. N Engl J Med. 2022;387(1):35-44. Epub 20220622. doi: 10.1056/NEJMoa2201422. PubMed PMID: 35731912; PMCID: PMC10361070.
  2. Peregrin T. Dr. Bartley P. Griffith Discusses Landmark Pig Heart Transplant. American College of Surgeons. 2022.
  3. System UoMM. University of Maryland School of medicine faculty scientists and clinicians perform historic transplant of porcine heart into adult human with end-stage heart disease. Press release. Press Release 2022.
  4. RC R. Patient in groundbreaking heart transplant dies. New York Times 2022.
  5. Anand RP, Layer JV, Heja D, Hirose T, Lassiter G, Firl DJ, Paragas VB, Akkad A, Chhangawala S, Colvin RB, Ernst RJ, Esch N, Getchell K, Griffin AK, Guo X, Hall KC, Hamilton P, Kalekar LA, Kan Y, Karadagi A, Li F, Low SC, Matheson R, Nehring C, Otsuka R, Pandelakis M, Policastro RA, Pols R, Queiroz L, Rosales IA, Serkin WT, Stiede K, Tomosugi T, Xue Y, Zentner GE, Angeles-Albores D, Chris Chao J, Crabtree JN, Harken S, Hinkle N, Lemos T, Li M, Pantano L, Stevens D, Subedar OD, Tan X, Yin S, Anwar IJ, Aufhauser D, Capuano S, Kaufman DB, Knechtle SJ, Kwun J, Shanmuganayagam D, Markmann JF, Church GM, Curtis M, Kawai T, Youd ME, Qin W. Design and testing of a humanized porcine donor for xenotransplantation. Nature. 2023;622(7982):393-401. doi: 10.1038/s41586-023-06594-4.
  6. Niu D, Wei HJ, Lin L, George H, Wang T, Lee IH, Zhao HY, Wang Y, Kan Y, Shrock E, Lesha E, Wang G, Luo Y, Qing Y, Jiao D, Zhao H, Zhou X, Wang S, Wei H, Güell M, Church GM, Yang L. Inactivation of porcine endogenous retrovirus in pigs using CRISPR-Cas9. Science. 2017;357(6357):1303-7. Epub 20170810. doi: 10.1126/science.aan4187. PubMed PMID: 28798043; PMCID: PMC5813284.
  7. Kozlov M. Monkey survives for two years after gene-edited pig-kidney transplant. Nature. 2023;622(7983):437-8. doi: 10.1038/d41586-023-03176-2. PubMed PMID: 37821613.
  8. Health NL. Two-Month Study of Pig Kidney Xenotransplantation Gives New Hope to the Future of the Organ Supply. RESEARCH, INNOVATION, PRESS RELEASES. 2023.
  9. Rabin RC. Second Maryland Man to Receive an Altered Pig’s Heart Has Died. The New York Times. 2023.
  10. Patience C, Takeuchi Y, Weiss RA. Infection of human cells by an endogenous retrovirus of pigs. Nat Med. 1997;3(3):282-6. doi: 10.1038/nm0397-282. PubMed PMID: 9055854.
  11. Montgomery RA, Stern JM, Lonze BE, Tatapudi VS, Mangiola M, Wu M, Weldon E, Lawson N, Deterville C, Dieter RA, Sullivan B, Boulton G, Parent B, Piper G, Sommer P, Cawthon S, Duggan E, Ayares D, Dandro A, Fazio-Kroll A, Kokkinaki M, Burdorf L, Lorber M, Boeke JD, Pass H, Keating B, Griesemer A, Ali NM, Mehta SA, Stewart ZA. Results of Two Cases of Pig-to-Human Kidney Xenotransplantation. N Engl J Med. 2022;386(20):1889-98. doi: 10.1056/NEJMoa2120238. PubMed PMID: 35584156.
  12. Moazami N, Stern JM, Khalil K, Kim JI, Narula N, Mangiola M, Weldon EP, Kagermazova L, James L, Lawson N, Piper GL, Sommer PM, Reyentovich A, Bamira D, Saraon T, Kadosh BS, DiVita M, Goldberg RI, Hussain ST, Chan J, Ngai J, Jan T, Ali NM, Tatapudi VS, Segev DL, Bisen S, Jaffe IS, Piegari B, Kowalski H, Kokkinaki M, Monahan J, Sorrells L, Burdorf L, Boeke JD, Pass H, Goparaju C, Keating B, Ayares D, Lorber M, Griesemer A, Mehta SA, Smith DE, Montgomery RA. Pig-to-human heart xenotransplantation in two recently deceased human recipients. Nat Med. 2023;29(8):1989-97. Epub 20230724. doi: 10.1038/s41591-023-02471-9. PubMed PMID: 37488288.
  13. Singh R, Gupta N, Vanathi M, Tandon R. Corneal transplantation in the modern era. Indian J Med Res. 2019;150(1):7-22. Epub 2019/10/02. doi: 10.4103/ijmr.IJMR_141_19. PubMed PMID: 31571625; PMCID: PMC6798607.
  14. Whitney Stuard EO, Joey Whelihan, Patrick Loehr, Samantha Rea, Bennett Vogt, Phi Luong, Zainab Atiq, Omer Ashruf, Medical Student. Corneal Transplant, Not All the Rules Prevent Blindness. International Journal of Eye Banking 2021;9(3).
  15. Gain P, Jullienne R, He Z, Aldossary M, Acquart S, Cognasse F, Thuret G. Global Survey of Corneal Transplantation and Eye Banking. JAMA Ophthalmol. 2016;134(2):167-73. Epub 2015/12/04. doi: 10.1001/jamaophthalmol.2015.4776. PubMed PMID: 26633035.
  16. Lewis T. Milestone Pig-to-Human Heart Transplant May Pave the Way for Broader Trial. Scientific American. 2023.

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