Genetically engineered pig hearts successfully transplanted into two brain-dead humans
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A team at NYU Langone Health successfully transplanted two genetically engineered pig hearts into recently deceased humans in June and July, part of an effort to create a xenotransplantation protocol for people with heart disease.
The two xenotransplants were performed June 16 and July 6 with two recently deceased donors maintained on ventilator support at NYU Langone’s Tisch Hospital. The team of surgeons then monitored heart function for 3 days for each donor.
The hearts were procured from pigs that had 10 genetic modifications, including four porcine gene “knockouts” to prevent rejection and abnormal organ growth as well as six human transgenes to promote expression of proteins that regulate important biologic pathways that can be disrupted by incompatibilities between pigs and humans, according to an institution press release.
In a press conference, Nader Moazami, MD, surgical director of heart transplantation at the NYU Langone Transplant Institute, who led the investigational procedures, said the hearts were evaluated for functionality over 72 hours; there were no early signs of organ rejection observed.
“The heart function was completely normal with excellent contractility,” Moazami said. “We did have to make some surgical modifications at the time of transplantation; part of that is because the pig heart is very similar but is not identical to the human [heart]. Part of that was because in the first operation, the heart was slightly undersized. Nevertheless, we learned a tremendous amount from the first operation. When that experience was translated to the second operation, [the heart] performed even better.”
Moazami said both hearts functioned normally with standard posttransplant medications and without additional mechanical support. Moazami said researchers also used a new infectious disease protocol and did not detect the presence of porcine cytomegalovirus in either transplant case.
“This is a milestone and a steppingstone in the right direction for some day making this clinically applicable to save the lives of many individuals,” Moazami said during the press conference.
The successful procedures come after surgeons at NYU successfully performed two kidney xenotransplants in September and November 2021.
Shortage of donor hearts
There are 6 million people with HF in the United States; about 100,000 of those have end-stage HF, yet only about 3,500 heart transplants are performed in the U.S. every year, according to Alex Reyentovich, MD, medical director of heart transplantation and director of the NYU Langone Advanced Heart Failure Program.
“Many people are dying waiting for a heart,” Reyentovich said during the press conference. “Xenotransplantation has the capability of addressing some of those supply limitations and saving lives.”
Reyentovich said these procedures were “the first of many steps” to design a protocol for a phase 1 trial for xenotransplantation in living human recipients.
“These are the first steps in developing a deep understanding of the mechanical, molecular and immunologic aspects of xenoheart transplantation and the feasibility of utilizing standard clinical practice and tools to do so,” Reyentovich said.
Decedent model offers ‘different focus’
As Healio previously reported, a man who became the first in the world to receive a genetically modified pig’s heart died March 8, just 2 months after receiving a procedure that was hailed as a milestone for xenotransplantation. The man, David Bennett, aged 57 years, had terminal heart disease and was deemed ineligible for a conventional heart transplant.
Performing such a procedure in a living human being calls for a different focus, according to Robert A. Montgomery, MD, DPhil, the H. Leon Pachter, MD, Professor and chair of the department of surgery at NYU Grossman School of Medicine and director of the NYU Langone Transplant Institute. That focus is keeping the person alive and comfortable, helping them to recover and participate in rehabilitation.
“For these studies in the recently deceased, it is a completely different focus,” Montgomery said. “The focus is learning, studying, measuring and trying to unravel what is going on in this brand-new, incredible technology that is so complicated. In these studies, we are able to intensively look at tissue and blood samples in a much deeper analysis.
“The advantage of doing decedent work is we can understand the human response to a pig organ in a detail that we can’t obtain any other way,” Montgomery said. “We want to go into phase 1 trials with as much information as we can possibly have.”
Montgomery, also the recipient of a heart transplant performed by the same NYU Langone team, said the successful procedures held special significance for him.
“It was one of the most incredible things to see a pig heart pounding away and beating inside the chest of a human being,” Montgomery said. “It is a great privilege for me to have witnessed that in my lifetime.”
A goal going forward is to lengthen the period of study beyond 3 days to gain more information on the adaptive immune system while moving toward a phase 1 trial, Montgomery said.
Raising awareness of body donation
The surgeons noted that whole-body donation after death for the purpose of breakthrough studies represents a new pathway that allows an individual’s altruism to be realized after brain-death declaration in circumstances in which their organs or tissues are not suitable for transplant.
The two deceased patients had previously expressed interest in organ donation; however, their organs were not viable for transplantation due to illness or other injuries, Reyentovich told Healio.
“These are both individuals who wanted to donate organs but were not able to,” Reyentovich told Healio. “The generosity of the families and the decedents wanting to give back were the most important steps.”
Montgomery said although the individuals were recently deceased, the xenotransplantation procedures still needed to be completed in patients who could tolerate it.
“In some instances, brain death triggers certain responses in the body,” Montgomery told Healio. “We see a certain percentage of brain-dead donors have a response to brain death where they become hyperinflammatory and unstable with BP and heart rate. Those kinds of things, that hyperinflammation, the ‘storm’ of mediators that can be released, can overlap with the responses we see in rejection, enhancing background ‘noise.’”
The team noted that these two donors showed no signs of a hyperinflammatory state, making them ideal candidates.
“They were profoundly perfect subjects, where we can really just look at the response [to the transplants],” Montgomery told Healio. “Part of that is just really good care by our intensivists, paying attention to all the details and stabilizing the donors.”
The hearts used in these procedures were procured from pigs engineered by Revivicor, a subsidiary of United Therapeutics Corp., which provided funding for this research.
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