History, Recent Advances, and Ethical Controversies of Solid Organ Xenotransplantation: Review and Implications for Future Clinical Trials
DOI:
https://doi.org/10.65539/by7zym91Keywords:
xenotransplantation, solid organ transplantation, genetically engineered pigs, clinical trials, bioethicsAbstract
Solid organ xenotransplantation has re-emerged as a potential solution to the persistent shortage of human donor organs. This review traces the field’s evolution from early chimpanzee and baboon grafts to today’s genetically engineered pig donors and long-surviving porcine kidney and heart xenografts in primate models. It summarizes key genetic modifications, immunosuppressive strategies, and recent milestone procedures, including decedent pig-to-human kidney transplants and the first compassionate-use pig heart transplant. The article also examines ethical challenges around zoonotic infection risk, lifetime surveillance of trial participants, patient selection, pediatric trials, and the use of animals, arguing for carefully designed early-phase clinical trials that balance societal benefit with participant protections.
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References
Organ Procurement and Transplantation Network. Organ Donation Statistics. Health Resources & Services Administration; 2022. (Accessed June 20, 2022 at https://www.organdonor.gov/learn/organ-donation-statistics)
Colvin M, Smith JM, Ahn Y, et al. OPTN/SRTR 2020 Annual Data Report: Heart. Am J Transplant. 2022;22 Suppl 2:350-437. DOI: https://doi.org/10.1111/ajt.16977
Lentine KL, Smith JM, Hart A, et al. OPTN/SRTR 2020 Annual Data Report: Kidney. Am J Transplant. 2022;22(S2):21-136. DOI: https://doi.org/10.1111/ajt.16982
Ekser B, Cooper DKC, Tector AJ. The need for xenotransplantation as a source of organs and cells for clinical transplantation. Int J Surgery. 2015;23:199-204. DOI: https://doi.org/10.1016/j.ijsu.2015.06.066
Mou L, Chen F, Dai Y, et al. Potential alternative approaches to xenotransplantation. Int J Surgery. 2015;23:322-326. DOI: https://doi.org/10.1016/j.ijsu.2015.06.085
Cooper DKC, Keogh AM, Brink J, et al. Report of the xenotransplantation advisory committee of the international society for heart and lung transplantation. J Heart Lung Transplant. 2000;19(12):1125-1165. DOI: https://doi.org/10.1016/S1053-2498(00)00224-2
Reemtsma K, Mccracken BH, Schegel JU. Renal Heterotransplantation in Man: Ann Surg. 1964;160(3):384-410. DOI: https://doi.org/10.1097/00000658-196409000-00006
Starzl TE, Marchioro TL, Peters GN, et al. Renal Heterotransplantation from Baboon to Man: Experience with 6 Cases. Transplantation. 1964;2(6):752-776. DOI: https://doi.org/10.1097/00007890-196411000-00009
Hardy JD, Kurrus FD, Chavez CM, et al. Heart Transplantation in Man. Developmental Studies and Report of a Case. JAMA. 1964;188:1132-1140. DOI: https://doi.org/10.1001/jama.1964.03060390034008
Bailey LL, Nehlsen-Cannarella SL, Concepcion W, Jolley WB. Baboon-to-human cardiac xenotransplantation in a neonate. JAMA. 1985;254(23):3321-3329. DOI: https://doi.org/10.1001/jama.1985.03360230053022
Cozzi E, White DJG. The generation of transgenic pigs as potential organ donors for humans. Nat Med. 1995;1(9):964-966. DOI: https://doi.org/10.1038/nm0995-964
Taniguchi S, Cooper DK. Clinical xenotransplantation: past, present and future. Ann R Coll Surg Engl. 1997;79(1):13-19.
Galili U. Interaction of the natural anti-Gal antibody with α-galactosyl epitopes: a major obstacle for xenotransplantation in humans. Immunol Today. 1993;14(10):480-482. DOI: https://doi.org/10.1016/0167-5699(93)90261-I
Oriol R, Ye Y, Koren E, et al. Carbohydrate antigens of pig tissues reacting with human natural antibodies as potential targets for hyperacute vascular rejection in pig-to-man organ xenotransplantation. Transplantation. 1993;56(6):1433-1442. DOI: https://doi.org/10.1097/00007890-199312000-00031
Lai L, Kolber-Simonds D, Park KW, et al. Production of α-1,3-Galactosyltransferase Knockout Pigs by Nuclear Transfer Cloning. Science. 2002;295(5557):1089-1092. DOI: https://doi.org/10.1126/science.1068228
Phelps CJ, Koike C, Vaught TD, et al. Production of α1,3-Galactosyltransferase-Deficient Pigs. Science. 2003;299(5605):411-414. DOI: https://doi.org/10.1126/science.1078942
Kuwaki K, Tseng YL, Dor FJMF, et al. Heart transplantation in baboons using α1,3-galactosyltransferase gene-knockout pigs as donors: initial experience. Nat Med. 2005;11(1):29-31. DOI: https://doi.org/10.1038/nm1171
Platt JL, Cascalho M. The Future of Transplantation. N Engl J Med. Published online June 22, 2022:NEJMe2207105.
Cooper DKC, Hara H, Iwase H, et al. Justification of specific genetic modifications in pigs for clinical organ xenotransplantation. Xenotransplantation. 2019;26(4). DOI: https://doi.org/10.1111/xen.12516
Azimzadeh AM, Kelishadi SS, Ezzelarab MB, et al. Early graft failure of GalTKO pig organs in baboons is reduced by expression of a human complement pathway-regulatory protein. Xenotransplantation. 2015;22(4):310-316. DOI: https://doi.org/10.1111/xen.12176
Iwase H, Ekser B, Satyananda V, et al. Pig-to-baboon heterotopic heart transplantation - exploratory preliminary experience with pigs transgenic for human thrombomodulin and comparison of three costimulation blockade-based regimens. Xenotransplantation. 2015;22(3):211-220. DOI: https://doi.org/10.1111/xen.12167
Cooper DKC, Ezzelarab M, Iwase H, Hara H. Perspectives on the Optimal Genetically Engineered Pig in 2018 for Initial Clinical Trials of Kidney or Heart Xenotransplantation. Transplantation. 2018;102(12):1974-1982. DOI: https://doi.org/10.1097/TP.0000000000002443
Längin M, Mayr T, Reichart B, et al. Consistent success in life-supporting porcine cardiac xenotransplantation. Nature. 2018;564(7736):430-433. DOI: https://doi.org/10.1038/s41586-018-0765-z
Higginbotham L, Mathews D, Breeden CA, et al. Pre-transplant antibody screening and anti-CD154 costimulation blockade promote long-term xenograft survival in a pig-to-primate kidney transplant model. Xenotransplantation. 2015;22(3):221-230. DOI: https://doi.org/10.1111/xen.12166
Iwase H, Liu H, Wijkstrom M, et al. Pig kidney graft survival in a baboon for 136 days: longest life-supporting organ graft survival to date. Xenotransplantation. 2015;22(4):302-309. DOI: https://doi.org/10.1111/xen.12174
Iwase H, Hara H, Ezzelarab M, et al. Immunological and physiological observations in baboons with life-supporting genetically engineered pig kidney grafts. Xenotransplantation. 2017;24(2):e12293. DOI: https://doi.org/10.1111/xen.12293
Mohiuddin MM, Corcoran PC, Singh AK, et al. B-Cell Depletion Extends the Survival of GTKO.hCD46Tg Pig Heart Xenografts in Baboons for up to 8 Months: Anti-CD20 Mediate Long-Term Xenograft Survival. Am J Transplant. 2012;12(3):763-771. DOI: https://doi.org/10.1111/j.1600-6143.2011.03846.x
Mohiuddin MM, Singh AK, Corcoran PC, et al. Role of anti-CD40 antibody-mediated costimulation blockade on non-Gal antibody production and heterotopic cardiac xenograft survival in a GTKO.hCD46Tg pig-to-baboon model. Xenotransplantation. 2014;21(1):35-45. DOI: https://doi.org/10.1111/xen.12066
Mohiuddin MM, Singh AK, Corcoran PC, et al. Chimeric 2C10R4 anti-CD40 antibody therapy is critical for long-term survival of GTKO.hCD46.hTBM pig-to-primate cardiac xenograft. Nat Commun. 2016;7(1):11138. DOI: https://doi.org/10.1038/ncomms11138
Kim SC, Mathews DV, Breeden CP, et al. Long‐term survival of pig‐to‐rhesus macaque renal xenografts is dependent on CD4 T cell depletion. Am J Transplant. 2019;19(8):2174-2185. DOI: https://doi.org/10.1111/ajt.15329
Porrett PM, Orandi BJ, Kumar V, et al. First clinical‐grade porcine kidney xenotransplant using a human decedent model. Am J Transplant. 2022;22(4):1037-1053. DOI: https://doi.org/10.1111/ajt.16930
Montgomery RA, Stern JM, Lonze BE, et al. Results of Two Cases of Pig-to-Human Kidney Xenotransplantation. N Engl J Med. 2022;386(20):1889-1898. DOI: https://doi.org/10.1056/NEJMoa2120238
Reardon S. First pig-to-human heart transplant: what can scientists learn? Nature. 2022;601(7893):305-306. DOI: https://doi.org/10.1038/d41586-022-00111-9
Griffith BP, Goerlich CE, Singh AK, et al. Genetically Modified Porcine-to-Human Cardiac Xenotransplantation. N Engl J Med. Published online June 22, 2022:NEJMoa2201422.
Sykes M, d'Apice A, Sandrin M, IXA Ethics Committee. Position paper of the Ethics Committee of the International Xenotransplantation Association. Transplantation. 2004;78(8):1101-1107. DOI: https://doi.org/10.1097/01.TP.0000142886.27906.3E
Smetanka C, Cooper DKC. The ethics debate in relation to xenotransplantation. Rev Sci Tech. 2005;24(1):335-342. DOI: https://doi.org/10.20506/rst.24.1.1574
Sautermeister J, Mathieu R, Bogner V. Xenotransplantation-theological-ethical considerations in an interdisciplinary symposium. Xenotransplantation. 2015;22(3):174-182. DOI: https://doi.org/10.1111/xen.12163
Ebner K, Ostheimer J, Sautermeister J. The role of religious beliefs for the acceptance of xenotransplantation. Exploring dimensions of xenotransplantation in the field of hospital chaplaincy. Xenotransplantation. 2020;27(4). DOI: https://doi.org/10.1111/xen.12579
Mathieu R. Jewish ethics and xenotransplantation. Xenotransplantation. 2016;23(4):258-268. DOI: https://doi.org/10.1111/xen.12247
Padela AI, Duivenbode R. The ethics of organ donation, donation after circulatory determination of death, and xenotransplantation from an Islamic perspective. Xenotransplantation. 2018;25(3):1-12. DOI: https://doi.org/10.1111/xen.12421
Cleveland D, Adam Banks C, Hara H, et al. The Case for Cardiac Xenotransplantation in Neonates: Is Now the Time to Reconsider Xenotransplantation for Hypoplastic Left Heart Syndrome? Pediatr Cardiol. 2019;40(2):437-444. DOI: https://doi.org/10.1007/s00246-018-1998-1
Denner J. Xenotransplantation and porcine cytomegalovirus. Xenotransplantation. 2015;22(5):329-335. DOI: https://doi.org/10.1111/xen.12180
Knoll MF, Cooper DKC, Bottino R. How the COVID-19 pandemic may impact public support for clinical xenotransplantation in the United States? Xenotransplantation. 2020;27(5):e12623. DOI: https://doi.org/10.1111/xen.12623
Paradis K, Langford G, Long Z, et al. Search for Cross-Species Transmission of Porcine Endogenous Retrovirus in Patients Treated with Living Pig Tissue. Science. 1999;285(5431):1236-1241. DOI: https://doi.org/10.1126/science.285.5431.1236
Wynyard S, Nathu D, Garkavenko O, et al. Microbiological safety of the first clinical pig islet xenotransplantation trial in New Zealand. Xenotransplantation. 2014;21(4):309-323. DOI: https://doi.org/10.1111/xen.12102
Matsumoto S, Wynyard S, Giovannangelo M, et al. Long‐term follow‐up for the microbiological safety of clinical microencapsulated neonatal porcine islet transplantation. Xenotransplantation. 2020;27(6). DOI: https://doi.org/10.1111/xen.12631
Denner J. Why was PERV not transmitted during preclinical and clinical xenotransplantation trials and after inoculation of animals? Retrovirology. 2018;15(1):28. DOI: https://doi.org/10.1186/s12977-018-0411-8
Niu D, Wei HJ, Lin L, et al. Inactivation of porcine endogenous retrovirus in pigs using CRISPR-Cas9. Science. 2017;357(6357):1303-1307. DOI: https://doi.org/10.1126/science.aan4187
Einsiedel EF. Commentary: On the position paper of the Ethics Committee of the International Xenotransplantation Association. Transplantation. 2004;78(8):1110-1111. DOI: https://doi.org/10.1097/01.TP.0000142604.35960.71
PHS Guideline on Infectious Disease Issues in Xenotransplantation. Food and Drug Administration; 2001. (Accessed June 28, 2022 at https://www.fda.gov/media/73803/download)
First WHO Global Consultation on Regulatory Requirements for Xenotransplantation Clinical Trials Changsha, China, 19-21 November 2008. Xenotransplantation. 2009;16(2):61-63. DOI: https://doi.org/10.1111/j.1399-3089.2009.00520.x
Welin S. Starting clinical trials of xenotransplantation--reflections on the ethics of the early phase. J Med Ethics. 2000;26(4):231-236. DOI: https://doi.org/10.1136/jme.26.4.231
Cooper DKC, Pierson RN, Hering BJ, et al. Regulation of Clinical Xenotransplantation—Time for a Reappraisal. Transplantation. 2017;101(8):1766-1769. DOI: https://doi.org/10.1097/TP.0000000000001683
Hurst DJ, Padilla LA, Cooper DKC, Paris W. Scientific and psychosocial ethical considerations for initial clinical trials of kidney xenotransplantation. Xenotransplantation. 2022;29(1). DOI: https://doi.org/10.1111/xen.12722
Hurst DJ, Padilla LA, Walters W, et al. Paediatric xenotransplantation clinical trials and the right to withdraw. J Med Ethics. 2020;46(5):311-315. DOI: https://doi.org/10.1136/medethics-2019-105668
Cooper DKC, Wijkstrom M, Hariharan S, et al. Selection of Patients for Initial Clinical Trials of Solid Organ Xenotransplantation. Transplantation. 2017;101(7):1551-1558. DOI: https://doi.org/10.1097/TP.0000000000001582
Yamamoto T, Iwase H, Patel D, et al. Old World Monkeys are less than ideal transplantation models for testing pig organs lacking three carbohydrate antigens (Triple-Knockout). Sci Rep. 2020;10(1):9771. DOI: https://doi.org/10.1038/s41598-020-66311-3
Kozlov M. Clinical trials for pig-to-human organ transplants inch closer. Nature. Published online July 6, 2022. DOI: https://doi.org/10.1038/d41586-022-01861-2
Montgomery RA, Mehta SA, Parent B, Griesemer A. Next steps for the xenotransplantation of pig organs into humans. Nat Med. 2022;28(8):1533-1536. DOI: https://doi.org/10.1038/s41591-022-01896-y
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