Xenotransplantation

Xenotransplantation is the transplantation, implantation, or infusion into a human recipient of living cells, tissues, or organs from a nonhuman animal source, or of human body fluids, cells, tissues, or organs that have had ex vivo contact with live nonhuman animal cells, tissues, or organs.[1] The most actively pursued form is the transplantation of solid organs (notably kidneys and hearts) from genetically engineered pigs into humans. The approach is being developed primarily as a potential response to the persistent shortage of human organs for transplantation.[2] As of June 2026, multiple decedent (brain-dead recipient) studies and a small number of living-recipient transplants under expanded-access ("compassionate use") authorizations have been performed, and the first formal U.S. clinical trials of gene-edited pig kidneys have begun.[3][4]

This article addresses the science, history, regulation, and ethics of xenotransplantation. It does not provide medical advice.

Rationale: the organ shortage

The principal driver of xenotransplantation research is the gap between the demand for transplantable organs and the supply available from human donors. According to the U.S. Health Resources and Services Administration (HRSA), more than 100,000 people are on the national transplant waiting list at any given time, and a person is added to the list every several minutes; many die each day while waiting.[2] Most candidates are waiting for kidneys, and many patients with end-stage kidney disease who would benefit from a transplant never receive one.[4] A reliable, scalable supply of animal-derived organs has therefore been a longstanding goal in transplantation medicine.[3]

Source species: why pigs

Early attempts at organ xenotransplantation used nonhuman primates, including the widely publicized 1984 case of "Baby Fae" at Loma Linda University, an infant who received a baboon heart and died within about a month from rejection.[5] Nonhuman primates were subsequently largely abandoned as source animals because of the risk of cross-species infection, ethical concerns, slow breeding, small organ size relative to adult humans, and limited availability.[5][6]

Pigs are now the source species of choice. Their organs are anatomically and physiologically similar in size to those of humans, they breed rapidly and in large litters, they can be raised under controlled (designated-pathogen-free) conditions, and the phylogenetic distance from humans reduces (though does not eliminate) certain infection concerns associated with primates.[6] Pigs are also amenable to genetic engineering, allowing their organs to be modified to reduce human immune rejection.[6] Porcine tissue has a long clinical track record: glutaraldehyde-fixed pig heart valves (bioprosthetic valves) have been implanted in humans for valve replacement since the 1960s and 1970s, although these are chemically treated, nonliving tissue rather than living vascularized organs.[7]

Immunologic barriers

The transplantation of a living pig organ into a human triggers powerful immune responses that have historically been the central obstacle to the field.[8]

Hyperacute rejection and the alpha-Gal (Gal) epitope

The most immediate barrier is hyperacute rejection, which can destroy an unmodified pig organ within minutes to hours. It is driven by preformed human "natural" antibodies that bind to a sugar antigen on pig vascular endothelium known as the alpha-Gal epitope (galactose-alpha-1,3-galactose), produced by the pig enzyme alpha-1,3-galactosyltransferase, encoded by the GGTA1 gene.[8][9] Humans do not make this epitope and carry circulating anti-Gal antibodies; when these bind the pig endothelium they activate the complement system, causing rapid vascular injury, thrombosis, and graft loss.[8][9] For background on the underlying mechanisms, see transplant immunology.

Additional anti-pig antibodies

Beyond alpha-Gal, humans also react to other pig carbohydrate antigens, notably N-glycolylneuraminic acid (Neu5Gc, produced by the CMAH gene) and the Sda-like antigen (produced by B4GALNT2).[9] Knocking out all three genes (GGTA1, CMAH, B4GALNT2) produces a "triple-knockout" pig whose cells bind substantially less human antibody, reducing the rejection response further than alpha-Gal removal alone.[9]

Complement and coagulation dysregulation

When antibodies bind the graft, the complement cascade amplifies the injury, so complement regulation is a key target.[10] In addition, pig and human coagulation systems are incompletely compatible, and molecular incompatibilities between pig endothelial regulators and human clotting factors can cause coagulation dysregulation and microthrombosis, contributing to later forms of rejection.[9][10] These barriers, together with cellular (T-cell) and antibody-mediated rejection that can develop over weeks, are addressed through a combination of genetic engineering of the donor pig and intensive immunosuppression of the recipient.[8][9]

Genetic engineering of donor pigs

Modern xenotransplantation depends on multiplex genetic modification of source pigs, made practical by genome-editing tools including CRISPR-Cas9.[9][11] Typical modifications fall into several categories:[9]

• Carbohydrate-antigen knockouts. Inactivating GGTA1 (GTKO, removing alpha-Gal), and often also CMAH and B4GALNT2, to eliminate the principal pig antigens recognized by human antibodies.[9]
• Human transgenes. Inserting human genes to make the organ more compatible, including human complement-regulatory proteins (such as CD46, CD55, and CD59) and human coagulation/anti-inflammatory regulators (such as thrombomodulin), to dampen complement attack and microthrombosis.[9][10]
• Growth control. Inactivating the pig growth hormone receptor (GHR) so the organ does not continue growing to its native size after implantation.[12]
• PERV inactivation. Using CRISPR to inactivate copies of porcine endogenous retrovirus (see below).[11]

Two organ products illustrate the spectrum. The pig heart used in the first living-human heart transplant (2022), supplied by Revivicor (a subsidiary of United Therapeutics), carried 10 genetic edits: four pig genes inactivated (including alpha-Gal and the growth hormone receptor) and six human genes added.[12] United Therapeutics' investigational "UKidney" likewise derives from a 10-gene-edited pig (six human genes added, four pig genes knocked out), while eGenesis' kidney product (EGEN-2784) is a separately engineered, multiplex gene-edited porcine kidney that also incorporates PERV inactivation.[4][13]

Infectious risk: PERV and zoonosis

A distinctive safety concern in xenotransplantation is xenozoonosis: the possibility that an infectious agent could cross from the animal organ into the human recipient and potentially into the wider population.[1] Source pigs are bred and screened to be free of designated pathogens, but one agent cannot simply be screened away because it is embedded in the pig genome itself: porcine endogenous retrovirus (PERV), which is present in multiple copies in all pig cells and can infect human cells in vitro.[11]

In 2017, researchers led by groups associated with George Church and Luhan Yang reported using CRISPR-Cas9 to inactivate dozens of PERV copies in pig cells and to generate live PERV-inactivated cloned pigs, substantially reducing the theoretical transmission risk; this built on earlier 2015 work demonstrating genome-wide PERV inactivation in a pig cell line.[11] It remains unproven whether PERV transmits to humans in vivo, and no PERV transmission has been documented in human xenograft recipients to date; nonetheless, PERV inactivation and lifelong infectious-disease surveillance of recipients remain standard precautions.[11][14] A separate, unanticipated infection risk was highlighted in the first living-human pig heart transplant, in which the organ was later found to harbor latent porcine cytomegalovirus / porcine roseolovirus (PCMV/PRV) that may have contributed to the recipient's deterioration.[15]

Regulatory framework

In the United States, xenotransplantation products are regulated by the Food and Drug Administration (FDA) as biological products under section 351 of the Public Health Service (PHS) Act, with oversight by the Center for Biologics Evaluation and Research; clinical use requires an Investigational New Drug (IND) application reviewed by FDA before proceeding.[16] Individual compassionate-use cases have proceeded under FDA's expanded-access provisions.[12]

FDA guidance addresses source animals, product manufacturing, preclinical testing, and clinical-trial design, including the December 2003 guidance "Source Animal, Product, Preclinical, and Clinical Issues Concerning the Use of Xenotransplantation Products in Humans."[16] Infectious-disease safeguards are set out in the PHS "Guideline on Infectious Disease Issues in Xenotransplantation," which calls for measures such as informed consent that explains the PERV/zoonosis risk, and long-term recipient surveillance with retention of health records and biological specimens for approximately 50 years, reflecting the latency of persistent viral infections.[14] Internationally, the World Health Organization has urged that xenotransplantation proceed only under regulatory oversight and with national surveillance, and professional bodies such as the International Xenotransplantation Association (IXA) have issued consensus guidance on the conduct of clinical trials.[14][17]

Key milestones

The dates below are point-in-time facts that should be re-confirmed against primary sources; the field is moving quickly.

Bioprosthetic heart valves (1960s onward) Glutaraldehyde-treated porcine heart valves have been used to replace human heart valves for more than 50 years and remain in routine clinical use; these are chemically fixed, nonliving xenografts rather than living organ transplants.[7]

Baby Fae (1984) At Loma Linda University, an infant known as "Baby Fae" received a baboon heart and survived about 21 days before dying of rejection, an episode that shaped subsequent ethical and scientific debate and contributed to the shift away from primate donors.[5]

NYU decedent pig kidney study (September 25, 2021) A team led by Robert Montgomery at NYU Langone Health attached a genetically engineered (alpha-Gal-knockout, "GalSafe"/Revivicor) pig kidney to the blood vessels of a brain-dead, deceased individual maintained on a ventilator with family consent; the kidney produced urine and functioned without immediate hyperacute rejection during the roughly two-to-three-day observation. A second such procedure followed on November 22, 2021.[18]

First pig heart transplant into a living human (January 7, 2022) Surgeons led by Bartley Griffith and Muhammad Mohiuddin at the University of Maryland Medical Center transplanted a 10-gene-edited Revivicor pig heart into David Bennett Sr., 57, who was ineligible for a conventional transplant, under FDA expanded-access authorization. Bennett survived about two months and died on March 8, 2022; investigators subsequently reported that the organ carried latent porcine cytomegalovirus/roseolovirus that may have contributed to the outcome.[12][15][19]

Second Maryland pig heart transplant (September 20, 2023) The University of Maryland team performed a second pig heart xenotransplant, into Lawrence Faucette, 58. He died on October 30, 2023, roughly six weeks after surgery, with signs of rejection.[20]

First pig kidney transplant into a living recipient (March 2024) Surgeons at Massachusetts General Hospital transplanted a CRISPR gene-edited eGenesis pig kidney into Richard ("Rick") Slayman, 62, in March 2024, the first such procedure in a living person. He was discharged about two weeks later and died in mid-May 2024; the hospital reported no indication that his death resulted from the pig kidney.[21]

Towana Looney (November 25, 2024) Towana Looney, 53, received a 10-gene-edited pig kidney at NYU Langone Health, becoming at the time the longest-surviving recipient of a pig organ. The kidney was removed on April 4, 2025, after about 130 days following an acute rejection episode that occurred after her immunosuppression was reduced to treat an unrelated infection; she recovered after explantation.[22]

Other living-recipient and decedent cases (2024-2025) Additional living-recipient kidney transplants were performed at Massachusetts General Hospital, including Tim Andrews (eGenesis kidney, transplanted January 25, 2025), who became the longest-surviving recipient of a gene-edited pig organ, reported as surpassing roughly seven to nine months before the kidney was removed, and Bill Stewart (transplanted June 14, 2025).[13][23] Decedent (brain-dead recipient) studies of pig kidneys and hearts have continued at multiple centers to refine immunosuppression and gene-editing choices without risk to living patients.[18]

FDA clinical trials and IND pathway (2025-2026) On February 3, 2025, United Therapeutics announced FDA clearance of its IND for a clinical trial of the UKidney (a 10-gene-edited pig kidney), structured as a combined phase 1/2/3 study beginning with six end-stage-renal-disease patients and expandable to up to 50.[3] FDA also cleared eGenesis' IND for EGEN-2784, supporting a trial in patients with end-stage kidney disease.[13] As of late 2025, the first transplant in United Therapeutics' EXPAND trial (NCT06878560), the first formal U.S. clinical trial of gene-edited pig kidney transplantation, was performed at NYU Langone Health, marking the transition from individual expanded-access cases to enrolled clinical trials.[24] As of June 2026, these early-stage trials are ongoing and their outcomes are not yet established; trial status and enrollment figures should be re-confirmed against primary sources.[24]

Ethics and oversight

Xenotransplantation raises distinctive ethical questions beyond those of human-to-human transplantation.[17] Because recipients may carry a theoretical risk of transmitting an animal-derived infection, informed consent and long-term, potentially lifelong, surveillance are emphasized, and consent frameworks have considered the implications for recipients' close contacts.[14][17] Additional issues include the welfare and ethical use of genetically engineered source animals, equitable access if the technology succeeds, the appropriateness of expanded-access ("compassionate use") authorizations in patients with limited alternatives, and the design of trials that fairly balance individual benefit against population-level infection risk.[17] The World Health Organization and professional societies including the IXA have called for xenotransplantation to proceed only within robust national regulatory and surveillance systems.[14][17] See also organ donation for the broader context of organ supply and consent.

See also

• Organ transplantation
• Transplant immunology
• Organ donation
• CRISPR gene editing
• Porcine endogenous retrovirus
• Immunosuppression

References

• U.S. Food and Drug Administration. "Xenotransplantation" (definition and overview / regulatory framework). https://www.fda.gov/vaccines-blood-biologics/xenotransplantation
• Health Resources and Services Administration (HRSA), organdonor.gov. "Organ Donation Statistics." https://www.organdonor.gov/learn/organ-donation-statistics
• United Therapeutics Corporation. "United Therapeutics Announces FDA Clearance of its IND Application for the UKidney Xenotransplantation Clinical Trial," February 3, 2025. https://ir.unither.com/press-releases/2025/02-03-2025-120011819
• American Kidney Fund. "FDA greenlights first clinical trials for genetically modified pig kidney transplants in humans." https://www.kidneyfund.org/article/fda-greenlights-first-clinical-trials-genetically-modified-pig-kidney-transplants-humans
• "The history of cardiac xenotransplantation: early attempts, major advances, and current progress." PMC. https://pmc.ncbi.nlm.nih.gov/articles/PMC11235224/
• "Genetically engineered pigs for xenotransplantation: Hopes and challenges." PMC. https://pmc.ncbi.nlm.nih.gov/articles/PMC9878146/
• "Xenograft bioprosthetic heart valves: Past, present and future." ScienceDirect. https://www.sciencedirect.com/science/article/pii/S174391911500374X
• "Xenotransplantation: the importance of the Galalpha1,3Gal epitope in hyperacute vascular rejection." ScienceDirect. https://www.sciencedirect.com/science/article/pii/S0925443999000563
• "Genetically modified pigs with alpha1,3-galactosyltransferase knockout and beyond: a comprehensive review of xenotransplantation strategies." Frontiers in Immunology, 2025. https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2025.1663246/full
• "Aspects of the Complement System in New Era of Xenotransplantation." PMC. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9046582/
• Niu D, Wei H-J, Lin L, et al. "Inactivation of porcine endogenous retrovirus in pigs using CRISPR-Cas9." Science, 2017. https://www.science.org/doi/10.1126/science.aan4187 (see also PubMed: https://pubmed.ncbi.nlm.nih.gov/28798043/)
• University of Maryland Medical Center. "University of Maryland School of Medicine Faculty Scientists and Clinicians Perform Historic First Successful Transplant of Porcine Heart into Adult Human." January 2022. https://www.umms.org/ummc/news/2022/transplant-of-genetically-modified-pig-heart-into-human-patient
• eGenesis / CRISPR Medicine News. "eGenesis Receives FDA Clearance for Gene-Edited Pig Kidney Trial in End-Stage Kidney Disease Patients" and related coverage. https://crisprmedicinenews.com/news/egenesis-receives-fda-clearance-for-gene-edited-pig-kidney-trial-in-end-stage-kidney-disease-patient/
• U.S. Public Health Service / FDA. "PHS Guideline on Infectious Disease Issues in Xenotransplantation." https://www.fda.gov/regulatory-information/search-fda-guidance-documents/phs-guideline-infectious-disease-issues-xenotransplantation
• MIT Technology Review. "The xenotransplant patient who died received a heart infected with a pig virus," May 4, 2022. https://www.technologyreview.com/2022/05/04/1051725/xenotransplant-patient-died-received-heart-infected-with-pig-virus/
• U.S. Food and Drug Administration. "Source Animal, Product, Preclinical, and Clinical Issues Concerning the Use of Xenotransplantation Products in Humans" (Guidance for Industry, 2003). https://www.fda.gov/regulatory-information/search-fda-guidance-documents/source-animal-product-preclinical-and-clinical-issues-concerning-use-xenotransplantation-products
• "Pig organs in humans: a forum on xenotransplantation" (ethics and oversight review). PMC. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11409890/
• NYU Langone Health News. "Progress in Xenotransplantation Opens Door to New Supply of Critically Needed Organs" / "Two-Month Study of Pig Kidney Xenotransplantation." https://nyulangone.org/news/progress-xenotransplantation-opens-door-new-supply-critically-needed-organs
• Griffith BP, et al. "Genetically Modified Porcine-to-Human Cardiac Xenotransplantation." New England Journal of Medicine. https://www.nejm.org/doi/full/10.1056/NEJMoa2201422
• University of Maryland Medical Center / CNN. "In Memoriam: Lawrence Faucette" and "Second person to receive experimental pig heart transplant dies," October-November 2023. https://www.umms.org/ummc/news/2023/announcing-the-passing-of-lawrence-faucette ; https://www.cnn.com/2023/10/31/health/lawrence-faucette-second-pig-heart-transplant-dies
• Massachusetts General Hospital. "World's First Genetically-Edited Pig Kidney Transplant into Living Recipient Performed at Massachusetts General Hospital" (March 2024) and family/MGH statements (May 2024). https://www.massgeneral.org/news/press-release/worlds-first-genetically-edited-pig-kidney-transplant-into-living-recipient
• NYU Langone Health News / Science. "Pig Kidney Recipient Returns Home After Transplant Breakthrough at NYU Langone Health"; "Longest human transplant of pig kidney fails," 2024-2025. https://nyulangone.org/news/pig-kidney-recipient-returns-home-after-transplant-breakthrough-nyu-langone-health ; https://www.science.org/content/article/longest-human-transplant-pig-kidney-fails
• CBS Boston / Medscape. "Pig kidney transplant success leads to new clinical trial at Massachusetts General Hospital"; "Second Pig Kidney Transplant Success and FDA Trial Approval," 2025. https://www.cbsnews.com/boston/news/pig-kidney-transplant-mass-general-new-hampshire/
• NYU Langone Health News. "First Gene-Edited Pig Kidney Transplant Clinical Trial Begins at NYU Langone Health" (EXPAND trial, NCT06878560), 2025. https://nyulangone.org/news/first-gene-edited-pig-kidney-transplant-clinical-trial-begins-nyu-langone-health