Xenotransplantation trials will require adjusting expectations, experts say – STAT

On the heels of some important firsts this past year, xenotransplantation grafting animal organs into humans is on the cusp of crossing over into new territory: human trials.

In January, University of Maryland surgeons transplanted a pig heart into a 57-year-old man, who survived two months. And last fall, New York University doctors implanted pig kidneys into recently deceased individuals to show there wouldnt be immediate rejection of the organs. As exciting as these procedures were for researchers who have been trying to make xenotransplantation a reality, they highlighted the slow pace of clinical development, which has been stalled in primate studies for decades.

In order to move from preclinical work in monkeys to FDA-approved clinical trials in people, the transplant community will need to adjust its definition of success, Robert Montgomery, director of the NYU Langone Transplant Institute, said Thursday at the 2022 STAT Breakthrough Science Summit in New York City.

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Standard human-to-human organ transplants have remarkable success rates for some organs. A year after a kidney transplant, 95% of recipients are still alive, said Montgomery, who performed the pig-to-human kidney procedures last year. Xenotransplantation will necessarily take time to get to that same level, he said. Were going to have the equivalent of an Apollo One disaster.

But the current success rates are an unfair standard for xenotransplantation, he said, because they ignore the thousands who die of organ failure every year without being able to get a transplant. I think the reason weve been in the non-human primate model for 30 to 40 years is just that. That the step into humans has been so encumbered with the idea that you have to get equipoise or some type of an equivalent outcome, he said. But to me its apples to oranges. What were really talking about is the organ shortage.

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Were talking about the half of people who get listed [for a transplant] who die thats what we should be comparing this to, not to the success of the half that are lucky and get opportunity like myself and my brother to live.

Montgomery himself had to be resuscitated from seven episodes of cardiac arrest before he made it on the list to await a donor heart. He eventually received a heart transplant, as did one of his brothers, but he said the risk-reward calculation for venturing into human xenotransplant trials should include patients who died at every step in the process.

Every patient that dies on the waitlist, we should be just as aware of that death as someone who dies in the ICU after they get a heart transplant or a kidney transplant, he said.

In the case of kidney disease, the estimated 800,000 patients in the U.S. with end stage illness have two options: a transplant, which is unavailable to many, or dialysis, which is not a permanent solution, noted Megan Sykes, a Columbia University transplant immunobiologist who has pioneered methods for reducing cross-species organ rejection.

We have a temporary lifeline for people with end stage renal failure, but it really is temporary, said Sykes.

There are also reasons to believe xenotransplantation could work better in human trials than in monkeys, the panelists said. For one, monkeys used in research are smaller than adult humans, and are complicated to take care of. They are sensitive to therapies, and dont respond to certain immunosuppressant drugs that work well in humans. Plus, if organs could be more readily available than they currently are, fewer transplant recipients would be on their death bed, increasing the likelihood of a good outcome, Sykes said.

The transplants into the recently deceased patients at NYU offers a better proxy for live human transplants than the monkeys. Still, researchers cant monitor the success of such transplants long-term. So, we wouldnt be able to tell the patients exactly [the prognosis] unless we do the living cases and monitor for a year or two, said Insoo Hyun, director of research ethics at the Harvard Medical School Center for Bioethics.

The pig organs used in the recent transplants come from genetically edited pigs developed by Revivicor, intended to prevent organ rejection and make them safer for humans. Scientists have spent years fine-tuning and layering edits to the animal genes, but its still an open question how much genetic engineering is necessary, or if less is more, the panelists said. Montgomerys group used pig organs with one edit, while the Maryland team transplanted a pig organ with 10 edits.

Sykes wants the field to take a step back and assess how valuable or harmful each genetic tweak is. The Food and Drug Administration may be more receptive to organs with fewer edits.

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Xenotransplantation trials will require adjusting expectations, experts say - STAT