Xenotransplants Make Progress

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In a procedure designed to closely mimic a human-to-human kidney transplant, Jayme Locke, MD, MPH, director of the Division of Transplantation at The University of Alabama, Birmingham, and her colleagues tested the safety and feasibility of transplanting a genetically engineered pig kidney into a human patient with a non-functioning brain.

The results were reported in January 2022 and showed that the genetically modified pig kidneys did not trigger a hyper-rejection reaction, could support human blood pressure, and could produce urine (1). The procedure was one of a string of recent attempts to test the potential of using pig

In a procedure designed to closely mimic a human-to-human kidney transplant, Jayme Locke, MD, MPH, director of the Division of Transplantation at The University of Alabama, Birmingham, and her colleagues tested the safety and feasibility of transplanting a genetically engineered pig kidney into a human patient with a non-functioning brain.

The results were reported in January 2022 and showed that the genetically modified pig kidneys did not trigger a hyper-rejection reaction, could support human blood pressure, and could produce urine (1). The procedure was one of a string of recent attempts to test the potential of using pig organs as replacements for human organ transplants in preliminary human studies. Last fall, surgeons at New York University (NYU) Langone Health connected genetically modified pig kidneys outside of the body of two deceased donors maintained on ventilators (2). In early January, surgeons at the University of Maryland School of Medicine transplanted a genetically modified pig heart into a living man under a compassionate-use exemption from the US Food and Drug Administration (FDA) (3).

The procedures build on decades of xenotransplant research in non-human primates. According to leaders in the field, this research is progressing toward clinical trials. The hope among Locke and others is that xenotransplantation may help solve the shortage of kidneys available for transplant. Currently, there are approximately 800,000 people living with end stage kidney disease in the United States, but only approximately one-third of them have received a kidney transplant, according to data from the National Institute of Diabetes and Digestive and Kidney Diseases (4). There are approximately 90,000 patients on the waiting list for a kidney, and many will die or become ineligible for transplant during the average 4- to 5-year wait time.

“We’re all really humbled to be a small part of this,” Locke said. “We all have a common enemy, kidney failure, and we are trying to figure out how we can defeat it and help our patients have access to a cure—kidney transplant.”

The pigs used for the kidney transplants at The University of Alabama, Birmingham, and the heart transplant at the University of Maryland were not just any pigs. They were “clinical-grade” animals, raised and housed in highly controlled conditions designed to reduce risk that the pigs could inadvertently spread disease to a human recipient.

Revivicor, a fully owned subsidiary of United Therapeutics, is the company that developed the pigs and leveraged new technologies, including the gene-editing tool CRISPR-Cas9, which genetically engineers the pigs so their organs will be more likely to be accepted by a human recipient. Locke explained that four pig genes encoding carbohydrate antigens were knocked out to prevent the human immune system from immediately rejecting the organ. The pig growth hormone receptor gene was also removed to prevent the pig organ from outgrowing the available space in its new recipient. Six human genes were also inserted to help modulate the human immune response to the organ, reduce inflammation, and help prevent blood clots.

“[The changes] were designed to humanize the pig enough that the pig kidney could be tolerated with conventional immunosuppressive drugs used after human transplant,” Locke said.

Locke and her colleagues also developed an assay to test whether the donor pig and the human recipient were a match and whether the person had preexisting antibodies to pigs. The test predicted a match, which their procedure confirmed without risking a human life, she said.

Within 20 minutes, one of the kidneys was already producing urine, which surprised and excited the team, Locke said. The other organ also produced urine but not as much, and neither achieved creatinine clearance, she said. Locke said she and her colleagues did not expect to achieve either urine or creatine creatinine in a recipient because of physiological changes that occur after brain death. The experiment ended 3 days later after the patient experienced multi-organ failure.

The surgical team at NYU Langone also used pigs developed by Revivicor, but the animals underwent only one genetic change to knock out the pig antigen galactose-α-1,3-galactose (alpha-gal) to prevent immediate rejection, said Robert Montgomery, MD, DPhil, H. Leon Pachter, MD, Professor of Surgery and chair of the Department of Surgery at NYU Langone, who performed the surgeries. That genetic modification was made using a technology called homologous recombination. Additionally, the pig's thymus gland was fused to the kidney before the transplant to help “educate” the immune system, according to the university's announcement (2).

Instead of replicating a transplant procedure, the kidneys were attached outside of the body to blood vessels in the legs of the two recipients to allow close monitoring. Because of the short duration of the procedure—a little over 2 days—the recipients received only steroid medications and the drug mycophenolate mofetil. After both procedures, urine production and creatinine levels were similar to what would be seen after a human transplant, said Montgomery, who is also director of the NYU Langone Transplant Institute. He and his colleagues plan to conduct additional pre-clinical studies with patients who are on life support to monitor for signs of organ rejection over a longer period.

The procedure at the University of Maryland was conducted under a compassionate-use exemption from the FDA, which enables patients with life-threatening conditions to take experimental drugs or undergo experimental procedures (3). The patient was hospitalized with a life-threatening arrythmia and had been on extracorporeal membrane oxygenation for weeks. The patient did not qualify for a human heart transplant and was ineligible for an artificial heart pump.

The patient received traditional immunosuppressive drugs along with an experimental anti-CD40 medication after the pig heart transplant (5). Montgomery noted that many professionals in the field of xenotransplant suspect that anti-CD40 or related anti-CD154 medications will be essential for human xenotransplant based on results from studies in non-human primates.

“This is the culmination of years of highly complicated research to hone this technique in animals with survival times that have reached beyond nine months,” said Muhammad Mohiuddin, MD, professor of surgery at the University of Maryland School of Medicine and scientific director of its Cardiac Xenotransplantation Program, in a statement from the university (3). “The successful procedure provided valuable information to help the medical community improve this potentially life-saving method in future patients.”

At press time, more than 3 weeks after the procedure, the patient continued to do well.

“Every day that patient continues to thrive is a great day for that patient and a great day for the field [of xenotransplant] in general,” said Alfred Joseph Tector, MD, a transplant surgeon and professor of surgery at the University of Miami.

Although the preclinical studies in pig kidney transplantation in patients without brain function and the recent pig heart transplant in a living recipient may help build confidence in the potential of xenotransplants, they will not replace traditional clinical trials, Montgomery said.

A preliminary phase 1 clinical trial in a small number of human patients, who could choose to participate in the trial or choose an alternative treatment, conducted at a few transplant centers would be the necessary next step before more widespread human use, according to Montgomery. Already, several groups, including Locke's team at The University of Alabama, Birmingham, are working toward the goal of launching preliminary clinical trials.

Montgomery predicted the trials could begin in the next year with FDA approval. Such a trial would help determine if there are any other incompatibilities between a pig kidney and a human donor and whether a pig kidney would be able to perform functions beyond just toxin clearance, such as maintaining electrolyte balance, stimulating red blood cell development, and helping control blood pressure.

“All of these things would be watched really closely to see if the pig kidney would fully replace the function of a human kidney,” Montgomery said.

David Cooper, MD, PhD, a senior research fellow at the Center for Transplantation Sciences at Massachusetts General Hospital, agreed that preliminary clinical trials are a necessary next step toward xenotransplantation. He noted that studies in human patients without brain function will not be able to provide definitive answers on the function of transplanted pig kidneys in humans, because brain death causes overwhelming inflammation and poor oxygen use, and other hemodynamic and metabolic changes occur that could harm the transplanted kidney. Cooper was awarded a Kidney Innovation Accelerator (KidneyX) award from the US Department of Health and Human Services and the American Society of Nephrology in 2021 to expand his studies of genetically modified pig kidney transplants in non-human primates (6).

“What we need to do now is to be bold and do a few transplants in some patients who are carefully selected by a team that has experience in the [non-human primate] xenotransplant model,” Cooper said.

Some patients on dialysis who are waiting for a human kidney transplant might benefit from participating in a pig xenotransplant clinical trial if it could give them a break from dialysis for several months to 2 years, he suggested.

“The potential is there for patients to gain a lot,” Cooper said. “Patients always feel much better when they have a functioning kidney than when they are on dialysis.”

Tector cautioned that it is important to take all the steps that the FDA requires before moving forward toward a clinical trial—even if further clinical studies in non-human primates will be challenging. Among the necessary next steps are the need to determine the best immunosuppressive regimen to use in clinical trials, which he agrees will likely include anti-CD40 or anti-CD154 antibodies. Tector was also awarded a 2021 KidneyX award as part of a team from Makana Therapeutics (the Regenerative Medicine Division of Recombinetics), which is working on a genetically engineered triple-knockout pig (7).

Tector said the success of human transplants raises the bar for what the public and the FDA will expect from the results of the first xenotransplant clinical trial. He explained that early human-to-human transplants had a high fatality rate, and some patients only lived for a short period of time.

“We have the opportunity to help the first person right out of the blocks,” he said.

Cooper said he expects that if the clinical trials are successful then xenotransplants will undergo a steady evolution where they will progressively improve the way human transplants live. He noted that for the first time, using genetically modified pigs creates the opportunity to modify the donor, which could help reduce the need for posttransplant medications.

“It will revolutionize organ transplant,” he said.

For Montgomery, the stakes are very personal. He is a heart transplant recipient because of a rare genetic condition that affects members of his family. As such, he knows how difficult it is for patients awaiting a transplant.

“I’ve spoken to a lot of other patients, and we want to see progress,” he said. “It needs to be safe, well thought out, closely monitored, and regulated. But we do want to see this move forward.”

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