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Surgeons perform the world’s first genetically modified pig kidney transplant into a living human at Massachusetts General Hospital, on March 16, in Boston.
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What does the recent pig kidney transplant mean for the future of transplantation?

Massachusetts General Hospital via AP

What does the recent pig kidney transplant mean for the future of transplantation?

'Xenotransplantation has been cooking and boiling for a long time'

On March 16, a team of surgeons at Massachusetts General Hospital, part of Harvard Medical School, successfully transplanted a gene-edited pig kidney into 62-year-old Richard Slayman. The first time a pig kidney has been transplanted into a living person, experts are calling the procedure groundbreaking.

It’s also an opportunity to fell barriers in organ transplantation, say those in the field. More than 103,000 people are currently on the waiting list for an organ in the U.S., and 17 people die daily waiting for one.

“The wait-list here in Western Pennsylvania is about five years for a standard deceased donor kidney,” said Jennifer Carpenter, surgical director of the living donor kidney program at Allegheny General Hospital and a physician. “Living donation and all these new xenotransplants are really exciting for our field, because they help reduce that gap for those waiting for kidneys.”

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Disparities exist in organ transplantation, and even occur before getting on the wait-list. For decades, the threshold of a metric known as estimated glomerular flow rate was higher for Black Americans. That metric was recently recalculated.

A genetically modified pig's heart is transplanted into a human at the University of Maryland Medical Center on Jan. 7.
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Pittsburgh native Bartley Griffith is behind breakthrough pig heart transplant

“This actually improved African Americans’ standing on the wait-list, but there are still a lot of disparities in medicine,” said Carpenter. “This is one step forward in helping to eliminate that and getting people the organs they need.”

Pittsburgh, long a key player in transplant research and surgery, is part of a wave of advancements tackling the many challenges within the field.

Pittsburgh researchers have been making strides in transplantation and xenotransplantation (transplants that involve organs from other animals) for decades, notably with the arrival of Thomas E. Starzl. A pioneer of transplantation, he performed the first-ever liver transplant in 1963 and joined UPMC in 1981, where he continued to further the field until his death in 2017. His name anchors UPMC’s Thomas E. Starzl Transplantation Institute in Oakland.

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In 2022, David Kaczorowski, an associate professor of cardiothoracic surgery at Pitt, was part of the team that transplanted the first gene-edited pig heart into a man. And Martin Wijkstrom, associate professor of surgery at Pitt, has been transplanting pig kidneys into nonhuman primates for many years.

Wijkstrom successfully transplanted a gene-edited pig kidney into a baboon, which survived for 136 days. He published a paper on that transplant in the journal Xenotransplantation in 2015.

Collaboration across institutions is common, and many interviewed about xenotransplantation said they knew or had worked with each other at some point.

In fact, Pittsburgh native Bartley Griffith, who led the 2022 pig heart surgery, once worked as the chief of cardiothoracic surgery at Pitt School of Medicine before he moved to the University of Maryland Medical Center. There, he worked with Muhammad Mohiuddin, professor of surgery, director of the cardiac xenotransplantation program at the University of Maryland School of Medicine, and the president of the International Xenotransplantation Association, who was also involved in the 2022 pig heart transplantation.

Dr. Angus W. Thomson, right, distinguished professor of immunology and surgery at Pitt, with Helong Dai (center) and Angelica Perez-Gutierrez in his lab at the Thomas E. Starzl Transplantation Institute in 2017.
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Mohiuddin has worked in xenotransplantation for 33 years and also views the recent advancements as an opportunity to destroy disparities in medicine.

“Overall, I see a lot of promise in this procedure. We see on a routine basis these patients who have no options, who just go to hospice care and are waiting to die,” he said. “If we had unlimited availability of organs, we wouldn’t have to fight for an organ, and health disparities would dissipate. If we have xenotransplantation as a solution, everyone will have an equal chance of getting this organ.”

Melissa Mattola-Kiatos, a nursing practice specialist, removes the pig kidney from its box to prepare for transplantation at Massachusetts General Hospital on March 16.Melissa Mattola-Kiatos, a nursing practice specialist, removes the pig kidney from its box to prepare for transplantation at Massachusetts General Hospital on March 16.(Massachusetts General Hospital via AP)

A key difference about the recent pig-to-human transplants is the use of CRISPR-Cas9 technology, which the company eGenesis used to edit 69 genes in the pig kidney to optimize it for transplant. (Revivicor, the company that engineered the pig heart in the 2022 transplant, was once partly owned by UPMC.)

Could this transplant have been done without CRISPR? Andrew Adams, professor of surgery, chief in the division of transplant surgery at University of Minnesota, and spokesperson for the American Society of Transplantation, didn’t think so.

“CRISPR revolutionized the field of gene editing,” he said, referring to the technology created by scientists Emmanuelle Charpentier and Jennifer Doudna, who won a Nobel Prize in 2020. “Xenotransplantation has been around for a number of years, but it’s never been actualized. Genome editing techniques progressed over the years to be able to do this.”

Another novel aspect was the use of an experimental immunosuppressant, tegoprubart, an antibody developed to slow progression of the neurodegenerative disease ALS. Researchers found that tegoprubart could also be used for transplantation because the drug disrupts key signals that turn on and off the immune system. It’s the same antibody that was used in the recent pig heart transplantation, said Adams.

“The number one issue in transplantation is the immune system,” Carpenter said. “Kidneys are very sensitive to rejection. To modify these pigs is a huge step forward in terms of going from pig to human.”

The procedure remains an experimental one, with Slayman able to receive the pig kidney transplantation because of his severe condition. Previous reports said he had grown “despondent and depressed” in his current state, after a 2018 kidney transplant from a deceased donor had failed, and he developed complications on dialysis. The Food and Drug Administration’s expanded access protocol, reserved for patients who have run out of options, allowed for treatment in this case.

Mohiuddin hopes the success of the procedure will garner more interest and trust in xenotransplantation for other patients in similar positions as Slayman.

“If we show that this is an effective way of saving lives, patients will definitely accept it,” he said. “I’m hoping this procedure takes off and is getting a lot of interest from patients.”

What happens next is going to depend on the outcome of Slayman’s procedure, said Wijkstrom.

“In a way, the field has been waiting for the FDA to feel comfortable that this is an area worthy of investigation,” he said. “Xenotransplantation has been cooking and boiling for a long time. We understand immunosuppression much better.”

Clinical trials need to be run before this becomes a standard human procedure in the U.S.

“This is all still considered highly experimental,” said Carpenter. “Until hundreds to thousands of pig kidneys are transplanted in the U.S. and considered safe, this will not be accessible to Americans.”

And there’s work to be done, too, on promoting health, well-being and access to medical care — before someone gets to the point of needing an organ transplant.

“The two biggest contributors to kidney failure are untreated blood pressure and diabetes,” said Adams. “Many times, it’s a result of inadequate access to primary care that leads to some of these end outcomes. We need to do more work in this space.”

But this is a significant step forward, he said. “The reason they were able to do this is because of previous research in labs and because of funding.”

In order to receive funding, researchers need to convince governing bodies — and the public — that science and research are worth investing in, and that in the long run, that investment helps patients.

“Funding is always the limitation,” said Wijkstrom. “This technology has come so far; it could really have an impact on health care delivery.”

And gene-editing technology could continue to evolve: A team at Pitt is working on using mRNA technology to transform damaged liver cells back into healthy ones.

“We could actually cure end-stage organ disease before patients needed a transplant,” he said. “Pittsburgh is on the forefront of this cutting-edge technology.”

Hanna Webster: hwebster@post-gazette.com 

Correction: An earlier version of this story incorrectly linked a Pitt professor to transplantation of pig kidneys into brain-dead patients. The 2023 transplants were performed by teams at the University of Alabama and NYU Langone Health.

First Published: April 6, 2024, 9:30 a.m.
Updated: April 8, 2024, 4:10 p.m.

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