Xenotransplantation: Are we ready for clinical trials in humans?
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For this month’s Infectious Disease News cover story, we touched base with experts in transplant medicine and transplant infectious diseases to discuss recent challenges brought on by the pandemic and the country’s organ shortage crisis.
One potential solution to the organ shortage is xenotransplantation — transplanting organs from other species into humans.
Last year, a team at the University of Maryland Medical Center performed the first transplant of a genetically-modified pig heart into a 57-year-old man with terminal heart disease. The surgery was a success and hailed as a milestone, although the patient later died.
We asked Olivia Kates, MD, an assistant professor of medicine at the Johns Hopkins School of Medicine, and Douglas J. Anderson, MD, MS, FACS, an assistant professor at the University of Alabama at Birmingham and program director of the university’s abdominal transplant fellowship, if medicine is ready for clinical trials of xenotransplantation in humans.
Kates: We are becoming ready.
Xenotransplantation is not a new idea, but recent advances in genetic engineering, immunosuppression and organ preservation have made a new era in xenotransplantation possible.
One transplant from a genetically modified pig to a living human has already been performed, in January 2022, under an emergency use authorization from the FDA. This is not the same as a clinical trial but certainly contributed to new knowledge and inspired new goals in clinical xenotransplantation.
To get ready for clinical trials in living humans, researchers have had to develop or improve preclinical models. A great deal of work has gone into developing safer and more successful protocols for transplanting genetically modified pig organs into nonhuman primates, with increasing success. Researchers in a few centers have also transplanted these organs into deceased humans — people who have died and have no brain activity but who remain connected to an artificial breathing machine. This allows the human immune system to interact with the xenotransplant kidney and has shown that fast, “hyperacute” rejection — once a seemingly insurmountable barrier to xenotransplantation — can be avoided.
A clinical trial of xenotransplantation will not look like most clinical trials we know or can imagine. COVID-19 vaccine studies enrolled dozens, then hundreds, then many thousands of participants, all within 1 year. A xenotransplant clinical trial will begin with a very small number of patients, likely one at a time but certainly in the single digits, and follow this patient or patients for a year or more before adding any new patients. In my mind, this will look more like individual surgical innovations, where a patient and doctor agree to try something new. Imagine something like, “We’ve never taken out a tumor quite like this one before because the tumor is unique and the surgery could be risky, but let’s try to take it out to give you the best shot at recovering.” Decisions like this can happen in private, between the doctor and the patient, and unprecedented surgeries happen all the time. For xenotransplantation, this conversation will happen with the added oversight of the FDA, an institutional review board, an ethics committee and a team of experts who are participating in the research. There will be preset parameters for what types of patients might be considered, how patients should be counseled about the surgery and approached for consent, how the surgery and related treatments will happen and how patients will be treated and monitored.
In my mind, the biggest challenge is safety. A participant in a xenotransplant clinical trial will have to take on heavy known burdens — like surgery and medications — and face high unknown risks, like rejection, infection, transplant failure or other complications. A xenotransplant recipient may even die as a consequence of attempting the transplant.
It is unusual that we set up clinical trials for an intervention this risky. That’s why it is so important to maximize our learning from preclinical models and to work with a diverse team of experts and regulators to design a study that is as safe and fair as possible. We are definitely getting ready, but a real clinical trial may still be a few years away.
Anderson: Simply put, yes.
Xenotransplantation has the potential to end the biggest issue in transplantation — the shortage of donor organs. Sadly, many patients die while awaiting a lifesaving organ transplant. The use of animal organs could bridge this gap, providing organs to the thousands of patients currently waiting. The need is clear.
Historically, the immunologic issues from crossing the species barrier appeared insurmountable. However, remarkable progress has been made over the past few several years. CRISPR-Cas9 techniques have greatly reduced the barriers to genetic editing of source animals. Current state-of-the art studies are using donor animals with 10 genetic edits designed to increase the donor organs compatibility with the human immune system. In preclinical models of pig-to-nonhuman primate xenotransplantation, graft survival can now be measured in years rather than days.
However, we are rapidly approaching the point where the remaining questions about xenotransplantation can be answered only in a clinical trial. Because we have optimized the donor animals for humans, they are becoming less suited for our nonhuman primate models. The Parsons model, using a recently deceased human as the recipient of a xenograft, is inherently time-limited by the pathophysiology of brain death. Whether a xenotransplant can provide long-term function to a human recipient can be answered only in a clinical trial.
Using the Parsons model, it has been shown that hyperacute rejection of a xeno-kidney can be avoided and urine produced. The recent transplant of a xeno-heart at the University of Maryland demonstrated the graft would function, at least for a period of several weeks. These data provide enough preliminary evidence to suggest further trials may be successful.
As there is a clear need and the possibility of success, what are the risks? Studies from the Parsons model have not shown any evidence of chimerism or porcine endogenous retrovirus transmission in the recipient. The heart recipient did develop detectable levels of porcine cytomegalovirus. However, there are no reports of transmission to other individuals involved in the case. It is likely this can be avoided by careful serologic and nucleic acid screening of the donor animals. There is also evidence that being the recipient of a xenotransplant does not sensitize the patient to alloantigens. Thus, even if long-term xenograft function is not achieved, the xenograft could act as a bridge and the recipient could potentially still receive an allotransplant.
The need for additional donor organs is urgent. The potential for xenotransplant success has been demonstrated in preclinical work, and with careful planning, the risks appear to be manageable. Will xenotransplantation be the answer to the organ shortage? We won’t know until we try.
References:
- Adams AB, et al. Ann Surg. 2018;doi:10.1097/SLA.0000000000002977.
- Kim SC, et al. Am J Transplant. 2019;doi:10.1111/ajt.15329.
- Griffith BP, et al. N Engl J Med. 2022;doi:10.1056/NEJMoa2201422.
- Li Q, et al. Xenotransplantation. 2018;doi:10.1111/xen.12393.
- Montgomery RA, et al. N Engl J Med. 2022doi:10.1056/NEJMoa2120238.
- Porrett PM, et al. Am J Transplant. 2022;doi:10.1111/ajt.16930.
- Yamamoto T, et al. Sci Rep. 2020;doi:10.1038/s41598-020-66311-3.
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