Revivicor’s Montgomery County facility, and another under construction in Christiansburg, are set to supply hearts and organs from pigs for human transplantation.
Forty years after David Ayares made a breakthrough discovery about gene editing, his work with Southwest Virginia-based Revivicor is making international news.
Two men over the past two years have received hearts from pigs raised in Revivicor’s Montgomery County research and development facility. Each heart featured 10 genetic modifications to help them function in humans, and both men lived for more than a month.
In a parallel development, surgeons have transplanted kidneys from Revivicor pigs into multiple brain-dead patients, with one set functioning for 61 days in a study that ended on Sept. 13, according to Revivicor’s parent company, United Therapeutics.
Xenotransplantation, the term for animal-to-human organ transplants, is ascendent. Ayares said he has been working academically and commercially toward the necessary gene knockouts and gene additions his entire career, first with mice, then with “big mice” — pigs.
“I mean, it was all part of the same path,” Ayares, 63, said. “Surprisingly, I’ve been very focused on what I’ve been doing, and science doesn’t always go that way. … And so it’s really just been taking the technology one step at a time, starting in 1983 all the way to now.”
That year, the man who would become Revivicor’s president and chief researcher was working toward his Ph.D. at the University of Illinois Medical Center. There he discovered and proved that mammalian cells have the molecular machinery to carry out gene editing, he said.
From there, the path has included the company that cloned Dolly the sheep, and a corporate partnership with a woman who is striving for both physical and digital immortality. That woman, Martine Rothblatt, founded United Therapeutics, which bought Revivicor in 2011, giving Ayares’ company the ability to “accelerate the science,” he said.
“This has been my life’s work … developing transgenic model systems in the pharmaceutical industry, and then with Revivicor and United Therapeutics for the last 23 years,” Ayares said in a recent video conference interview. “So this is so exciting.”
United Therapeutics, which is based in Silver Spring, Maryland, and has operations in Research Triangle Park, North Carolina, believes that clinical studies could begin in 2025. The two recent heart xenotransplants were experimental, conducted with consent from patients who did not qualify for human heart transplants.
The company is constructing what it says is a clinical-scale, pathogen-free facility in Christiansburg that will produce pigs for further studies. Output will be about 125 organs per year, according to a news release. The building should be functional and supporting a pig population by early next year, said Dewey Steadman, who directs investor relations for United Therapeutics.
That population’s lineage will have begun nearby, at Revivicor’s facility.
The goal is to make a dent in the overwhelming need for transplantable organs. More than 100,000 people in the United States are on the organ transplant waiting list. Nearly 90,000 of them need kidneys and about 3,300 need hearts, according to the federal Health Resources and Services Administration.
Each day, 17 people die waiting for transplants. About 800,000 in the U.S. have kidney failure, and more than 560,000 kidney patients are on dialysis, according to the American Kidney Fund.
Once United Therapeutics sees survival in a human clinical study, it will build larger facilities at North Carolina’s Research Triangle Park and in two other locations closer to U.S. kidney- and heart-transplant centers, Steadman said.
“And so that would give us about 3,000 organs a year, which is just touching the surface of the demand,” he said.
Ultimately, the company will expect no complications from those organs, which will allow patients to live out their lives with them, he said.
A search for lungs
United Therapeutics founder Rothblatt’s career wasn’t about organ production and transplantation. That didn’t happen until she had a daughter in need. Rothblatt sold her interest in Sirius Satellite Radio — which eventually would become Sirius XM — 34 years ago, and soon was studying biology, according to The Washington Post. The reason: Her 5-year-old daughter, Jenesis, was diagnosed with pulmonary arterial hypertension, or high blood pressure in vessels supplying the lungs.
There is no cure, but some patients survive into their 50s with medical treatment, according to the National Library of Medicine. Rothblatt created United Therapeutics, and the FDA approved its pulmonary arterial hypertension drug, Remodulin, in 2002, Steadman said. She later bought a drug from Glaxo Wellcome that was known to have helped some patients yet was languishing, according to Forbes. She named it Orenitram — “Martine Ro” backwards — and the FDA approved it in 2013.
About 14,000 patients with various forms of pulmonary hypertension use the drug, and United’s pharma portfolio has made it a $2 billion-per-year company, Steadman said.
The satellite-expert-turned-biotech-CEO found a way to help her daughter as she simultaneously sought to expand the transplantable lung market. Jenesis Rothblatt, who works for United Therapeutics, has since switched to a drug that another company produces, Steadman said. The longer-term issue remains.
“Martine figured out pretty early on that the solution would be an unlimited supply of lungs for transplant,” Steadman said. “And one of those sources could be from pigs. … It’s easy to raise pigs. There’s millions of them raised every year for the food supply.
“Martine actually pursued a Ph.D. in medical ethics, and her dissertation was on the medical ethics of xenotransplantation. This was back in 2002. … Revivicor crossed our radar as one of the potential developers of this technology.”
Rothblatt was not available for an interview, Steadman said.
The company eventually realized that Revivicor’s kidneys and hearts, modified with gene editing, potentially could be xenotransplanted much sooner than pig lungs.
Rothblatt is a futurist who with her wife, Bina Aspen Rothblatt, started the Teresem Movement, which centers on extending life both organically and digitally. Bina Rothblatt contributed her personal information in 2014 to a company that uploaded the files to develop a robot, Bina48, that looks like a bust on a desktop and speaks with a digital assistant’s cadence while displaying rubbery facial expressions. Martine Rothblatt commissioned Bina48 and the same year wrote a book, “Virtually Human: The Promise and the Peril of Digital Immortality.”
One United Therapeutics board director is scientist and widely noted futurist Ray Kurzweil, whose books include “The Singularity Is Near: When Humans Transcend Biology.”
“She has to my knowledge a perfect track record in making [her] visions real,” Kurzweil told The Washington Post in a 2014 article.
A spinoff from Dolly
Ayares is a New Jersey native who grew up in the Chicago suburbs. He received a doctorate in molecular genetics at the University of Illinois Medical Center, then went to Massachusetts Institute of Technology for postdoctoral studies.
In the 1990s Ayares worked at Abbott Laboratories, where he started its first transgenic mouse facility, modeling human disease in mice, then at Baxter Healthcare, where he developed transgenic mice models for cancer and diabetes. After Baxter closed its gene therapy division, Ayares joined the U.S. division of Scotland’s PPL Therapeutics in 1997.
The year before, PPL had become famous for Dolly the sheep, the first mammal successfully cloned from an adult cell.
Among PPL’s acquisitions in that era was TransPharm, based at the Virginia Tech Corporate Research Center. Ayares came to Blacksburg after PPL hired him, and when the Scottish company closed in 2003, he founded Revivicor and kept offices at the Corporate Research Center.
Ayares said that grants and venture capital funded the new company. The leading investment came from the University of Pittsburgh and the leader of its liver program, Dr. Tom Starzl — widely known in the medical world as “the father of modern transplantation.”
“So our focus in 2003 through 2011 was whole organs, primarily heart, kidney and liver, as well as pancreatic islets for treating diabetes,” Ayares said.
Then United came along, and with it both Rothblatt’s desire for lungs that might extend her daughter’s life and financial security that allowed Revivicor to hone its focus on xenotransplantation science, Ayares said. Heart and kidney work would eventually return to the forefront. United on Dec. 13 bought yet another company, Minneapolis-based Miromatrix Medical, which is working on xenotransplantable livers and other products.
Meanwhile, xenotransplanted lungs have been working in baboons for up to a month, Ayares said. Challenges to using pig lungs in humans puts clinical studies much further down the road.
“And so while we still are interested in the lung, it’s just much more challenging because it’s the only organ that is exposed to the environment, the air, and so it’s prone to inflammatory events, et cetera,” he said.
United is studying the potential for 3D-printed lung scaffolds populated with human cells, as well as pig lungs with all pig cells edited out and replaced with human cells.
“So there’s multiple shots on goal there to try to achieve that,” Ayares said.
The surgeries and results
On Jan. 7, 2022, at the University of Maryland Medical Center, a terminal heart patient named David Bennett was the first person to receive a genetically modified porcine heart.
The U.S. Food and Drug Administration authorized the surgery under a compassionate use provision. The medical center took a pig from the 300-population Revivicor facility in Roanoke County and brought it to Baltimore, where it removed the heart and transplanted it to Bennett.
“It was either die or do this transplant,” Bennett, 57, said before the procedure, according to a University of Maryland Medical Center news release at the time. “I want to live. I know it’s a shot in the dark, but it’s my last choice.”
He died March 8. According to the Baltimore-based medical center, the xenotransplant had performed very well for several weeks with no signs of rejection. Bennett spent time with his family, participated in physical therapy and watched the Super Bowl with his therapist.
A variety of factors likely played a role in what doctors ultimately determined was heart failure, according to the report doctors published about three months after Bennett’s death. His poor pre-transplant health had left him severely immunocompromised, which limited doctors from using an effective anti-rejection regimen. A drug given twice to Bennett to prevent post-transplant infection likely triggered an immune response.
A latent virus in the pig heart — porcine cytomegalovirus, or PCMV — became active and “may have contributed to the dysfunction of the transplant,” the medical center said. There was no evidence that the virus had infected Bennett or spread beyond the heart.
“We’ve tried to raise pigs without CMV and we try to test to avoid CMV,” Steadman said. “This pig unfortunately had it, and it was latent in the pig. So, it’s kind of like when you get a cold sore, you’ll test positive for herpes, but when you don’t have a cold sore, you won’t test positive for herpes. So it’s very difficult to detect.”
He added: “We … learned about testing, obviously, for viruses. We’ve developed more on our side. We’ve developed more sensitive assays to be able to check the presence of pig viruses in the pigs before transplantation.”
Revivicor and the surgical team at University of Maryland would apply that lesson and others on Sept. 20 this year. Laurence Faucette, 58, was also found ineligible for a human heart transplant, and the FDA again granted compassionate use of the experimental surgery.
“We are once again offering a dying patient a shot at a longer life, and we are incredibly grateful to Mr. Faucette for his bravery and willingness to help advance our knowledge of this field,” said Dr. Bartley Griffith, who did both xenotransplants, according to a medical center news release. “We are hopeful that he will get home soon to enjoy more time with his wife and the rest of his loving family.”
He died Oct. 30. Doctors have yet to publish a report on their post-mortem findings.
Ayares said he met with Bennett about four weeks after the first surgery.
“And we talked and we cried a little bit, because it’s a very emotional thing,” Ayares said. “I got to meet David Bennett’s son … and the families of both David Bennett and Larry Faucette have just been incredible. I mean, they realize that their loved one is a hero.
“I would say their families are heroes as well, for wanting to advance the science so that mankind in general can benefit from this research and this development.”
There were no further procedures immediately planned for humans, Steadman said. In any case, it would be a sudden process. Identifying appropriate subjects and getting their consent are not planned out in advance, he said.
These transplants, despite their international high profile, are not the main objective for United Therapeutics and Revivicor. Instead, Revivicor is supplying organs to UM Medical and another Baltimore institution, Johns Hopkins University, who are doing baboon studies.
“Our primary focus is to move into a larger human study,” Steadman said.
At least two other companies, eGenesis and Makana Therapeutics, have their own pigs and are consulting with the FDA about how to get to the clinical trial stage, according to technologyreview.com.
Steadman said eGenesis recently announced long-term survival of about two years for non-human primates with pig kidneys.
“They’re there, and we’re watching them, and they’re learning from us, just as we’re learning from them,” Steadman said. “But this is one where there’s no way to meet the demand for it. So we encourage all comers to — if we can learn from them — to reach the market.”
________________
Corrections 10:45 a.m. Dec. 19: Revivicor’s working facility is in Montgomery County. David Ayares is no longer Revivicor’s CEO, but is its president and chief scientific officer. Martine Rothblatt founded United Therapies and owns shares in the company, which purchased Revivicor. Rothblatt launched the company with Remodulin, FDA-approved in 2002.
Move toward transplantable pig hearts also could help those with a tick-borne food allergy
First among crucial developments to deliver a pig’s heart that a human body won’t reject: stripping alpha-gal sugars from porcine cell surfaces.
Many who suffered a lone star tick bite and wound up allergic to meat know about alpha-gal syndrome. AGS — aka alpha-gal allergy, red meat allergy or tick bite meat allergy — is associated with that tick’s bite, and other ticks might cause it as well.
Beef, pork, lamb, venison, rabbit, other meats and their byproducts including gelatin and cow’s milk are typically off the menu for those who show the variety of AGS symptoms, which can include such fatal conditions as anaphylaxis.
It is unclear how many Americans are affected, though the Centers for Disease Control and Prevention reported more than 110,000 cases between 2010 and 2022.
The U.S. Food and Drug Administration in 2020 approved a gene alteration in a line of domestic pigs that knocked out the immune system stimulant alpha-gal (galactose-α-1,3-galactose) molecule and declared the pork safe to eat. The line in question came from the Revivicor facility in northern Roanoke County. The so-called GalSafe pigs may be used for food or human therapeutics, according to the FDA, but at Revivicor, raising hearts and kidneys for human transplants is top of the list.
The sugar offends not only when the tick-bitten bite into some pulled pork. It causes human transplant candidates to reject pig organs. So it had to go.
“We started out with the first cloned pigs in 2000, and then [in 2001] we generated the first cloned alpha-gal knockout pigs, and then systematically in the last 20 years have been enhancing the genetics by further inactivation of pig genes and addition of human genes,” said Revivicor’s CEO and lead researcher, David Ayares. “So we have pigs with one, four, seven, nine, 10 genetic modifications at our farm.”
In fact, Ayares was with PPL Therapeutics — the company that cloned Dolly the sheep — at that time, working out of the Virginia Tech Corporate Research Center. A couple of years later, he would incorporate Revivicor as Scotland-based PPL went out of business. Revivicor would retain the GalSafe pigs that Ayares developed with a team that included the University of Pittsburgh Medical Center’s Dr. Thomas Starzl, often called “the father of modern transplantation.”
Revivicor has a herd of GalSafe pigs in Iowa being used for studies, and the size has to be maintained, but meat is available only occasionally, said Dewey Steadman of Revivicor’s parent company, United Therapeutics.
“We’ve been providing it free of charge to alpha-gal patients who contact Revivicor and fill out a form to request samples,” Steadman said. “We haven’t gotten into food production because obviously we’re a pharma company, not a Smithfield Foods by any means.”
Revivicor has talked with other companies about producing the meat, but the economics don’t work out, he said. Ultimately, GalSafe pork is a tantalizing prospect that is also untenable for mass production.
“We’re well oversubscribed for available meat at this point, and we don’t want to set the expectation that it’s widely available,” Steadman said. “We may make more meat available in the distant future, but our team wants to keep their heads down and focused on getting xeno organs into clinical trials.”
As originally posted by Tad Dickens HERE.