December 2023

The second recipient of a genetically modified pig heart transplant passed away on October 30, 2023, survived for almost six weeks post-transplant. In comparison, the first patient who underwent a similar procedure lived for two months after the xenotransplant in 2022. Both recipients were in end-stage heart failure and deemed unsuitable for alternative treatments, leading to emergency authorization from the US Food and Drug Administration (FDA) in both cases. Acute rejection appeared to be the common cause of death in both instances. In the first case, antibody-mediated rejection was evident, and the presence of the porcine cytomegalovirus (PCMV) in the heart may have also contributed to transplant dysfunction; while the causes of failure in the second recipient were still under investigation.

The utilization of genetically modified animal organs, engineered to be less foreign to human recipients, serves as a strategy to alleviate the organ shortage. Recent cases of pig heart transplantation involved knocking out three genes responsible for rapid antibody-mediated rejection of pig organs, inserting six human genes to enhance immune acceptance, and modifying one gene to control excessive tissue growth in the pig heart. Additionally, the use of immunosuppressants further contributed to preventing rejection. Preclinical studies are critical to understand graft survival and screening for organs free of porcine infectious agents. Testing on genetically engineered pig hearts and refining immunosuppression in non-human primates has demonstrated rejection-free survival of cardiac xenografts for up to 945 days (Singh et al, 2022).

Recent challenges in patients underscore the complexities of xenotransplantation. It’s vital to recognize the existing guidelines and regulations guiding these procedures. The Public Health Service (PHS) Guideline on “Infectious Disease Issues in Xenotransplantation” was released by United States Public Health Service in January 2001, outlining principles for preventing and controlling infectious diseases related to xenotransplantation with a focus on public health safety. The discovery of a pig virus in the patient’s new heart in the first pig heart transplantation case aligned with the guideline’s emphasis on infectious disease issues. The FDA Center for Biologics Evaluation and Research (CBER) has issued guidance for sponsors of xenotransplantation clinical trials. The “Guidance for Industry: Source Animal, Product, Preclinical, and Clinical Issues Concerning the Use of Xenotransplantation Products in Humans” was finalized in April 2003, which was amended in December 2016, to replace the previous two guidance, the 1999 “Guidance for Industry: Public Health Issues Posed by the Use of Nonhuman Primate Xenografts in Humans” and the 2002 “Draft Guidance for Industry: Precautionary Measures to Reduce the Possible Risk of Transmission of Zoonoses by Blood and Blood Products from Xenotransplantation Product Recipients and Their Intimate Contacts”. This guidance provides updates on the production, testing and evaluation of xenotransplantation products, aiming to assist sponsors and applicants during protocol development and the submission preparation to the FDA. Aligned with the PHS Guideline, it includes additional recommendations on product issues and good manufacturing practices to prevent the introduction and spread of infectious agents of animal origin into the human population. For example, a list of agents for which all source animals should be screened, a list of appropriate diagnostic tests and protocols for monitoring disease and infectious agents are required. The World Health Organization (WHO) also published the “Second Global Consultation on Regulatory Requirements for Xenotransplantation Clinical Trials” in 2011, delineating the prevalent microorganisms found in swine that must be taken into account as potential sources of infection in recipients of human xenografts. This comprehensive list encompasses bacteria, parasites, fungi, and viruses, with PCMV among the viruses highlighted.

While xenotransplantation shows promise in addressing organ shortage, considerable progress is needed before animal organs can be a standard in medical care. This complex and evolving field requires ongoing research to refine techniques, enhance outcomes, and tackle challenges related to rejection and infectious risks. In addition, ensuring success and safety in human xenotransplantation necessitates strict adherence to ethical standards, regulatory guidelines, and continuous recipient monitoring.

References:

Singh AK, Griffith BP, Goerlich CE, Ayares D, Mohiuddin MM. The road to the first FDA-approved genetically engineered pig heart transplantation into human. Xenotransplantation. 2022;29(5):e12776. doi:10.1111/xen.12776

PHS Guideline on Infectious Disease Issues in Xenotransplantation, 2001. https://www.fda.gov/media/73803/download

Guidance for Industry: Source Animal, Product, Preclinical, and Clinical Issues Concerning the Use of Xenotransplantation Products in Humans, 2016. https://www.fda.gov/media/102126/download

Second WHO Global Consultation on Regulatory Requirements for Xenotransplantation Clinical Trials, 2011. https://iris.who.int/bitstream/handle/10665/341817/WHO-HTP-EHT-CPR-2011.01-eng.pdf?sequence=1&isAllowed=y