New York University (NYU) surgeons transplanted two genetically modified pig hearts into brain-dead individuals and found good heart function, with no signs of immediate rejection over a period of 72 hour observation.
The xenotransplants were performed on June 16 and July 6 at NYU Langone Tisch Hospital in New York City and featured 10 genetic modifications aimed at preventing rejection and stopping abnormal organ growth.
Robert Montgomery, MD, PhD, of NYU Langone Health, was part of the surgical team and told a press briefing on Tuesday that the procedure “held special meaning for me.” Montgomery is a heart transplant recipient.
“It was one of the most amazing things to see a pig’s heart beating and pounding in a human’s chest,” he said. “It is a great privilege for me to have witnessed this in my lifetime.”
The NYU team also developed a more sensitive test for porcine cytomegalovirus (pCMV), which was suspected to have played a role in problems with the first and only pig-to-human heart transplant by surgeons at the University. ‘University of Maryland at Baltimore earlier. this year, although the exact cause of the patient’s death 60 days after the transplant in this case remains unclear.
Montgomery explained why studies should still be done in deceased people when it has already been done in a human, David Bennett (57). He said that while the focus is on the patient in live xenotransplantation and on “keeping that individual alive and well”, performing tests on dead patients brain allows for “much deeper analysis of what’s going on,” including the ability to take regular tissue samples to better understand the immune response.
“During the transplant that happened to Mr. Bennett, it was a tremendous achievement to keep him alive for 2 months,” Montgomery said. “But in the end, we don’t know why that heart failed and why it died.”
Montgomery said his team’s next steps would be to assess the viability of the xenograft for more than 72 hours and continue to engage with the FDA in the pre-IND (investigational new drug application) phase in order to begin possibly phase I trials, which could be under way by 2025.
Alice Michael, longtime partner of Lawrence Kelly, 72, one of the NYU recipients, was also present at the press conference. Kelly was a Vietnam veteran who later worked as a welder. She described him as someone who liked to fix things, and when Michael was diagnosed with metastatic breast cancer, “he was so upset because he couldn’t fix my cancer”.
“It’s comforting to know that he [Kelly] was part of this research program and that it can help so many people,” Michael said.
Knock-Outs and Knock-Ins
The pair of surgeries used pig hearts that had 10 genetic changes, including four pig gene knockouts aimed at preventing rejection and abnormal organ growth, and six human transgenes, or knock-ins, to prevent rejection and other complications.
Montgomery said the inclusion of the inactivation of the porcine growth hormone receptor was essential, as observations in primate transplantation studies have shown that the porcine heart continues to grow after transplantation, which means that the organs have grown too large for the primate’s chest cavity and have become compressed. He added that this seemed to lead to the organs used in current procedures being somewhat undersized.
Surgical team member Nader Moazami, MD, Surgical Director of NYU Langone Heart Transplantation, said the group had to make surgical changes at the time of the transplant because the blood vessels were slightly too small and enlarge the blood vessels to accommodate the mismatch.
“Even though the blood flow was good, there was evidence that the amount of blood flow was not perfect enough,” Moazami said.
He explained that the mismatch was lessened in the second recipient (female, 64) because she was shorter and because the team had improved their adaptive surgical technique in the first procedure.
In both cases, heart function was “completely normal” on cardiac imaging during the 72-hour observation period, Moazami said.
The biopsies also showed no signs of early rejection, said team member Alex Reyentovich, MD, medical director of heart transplantation. Both patients received standard post-transplant medications.
Montgomery said the team worked with United Therapeutics to improve the sensitivity of the pCMV test in response to Bennett’s case. Although pCMV was not detected in Bennett’s cells, it was detected in his blood and appeared to be confined to pig hearts. It had not been detected during the pre-transplant screening.
The Bennett Experience
It’s unclear exactly what went wrong in Bennett’s transplant case; he developed an infection 43 days after transplant and the donor pig was suspected to have latent pCMV infection. According to a New England Journal of Medicine (NEJM) report, Bennett recovered from the infection and was able to sit in a chair on day 48 after the transplant. But his condition changed on day 49, and Bennett was put on extracorporeal membrane oxygenation (ECMO). It was the first time there was evidence of a drop in cardiac output since the transplant, wrote Bartley P. Griffith, MD, of the University of Maryland, and colleagues.
Although they reported that there was no evidence of rejection at day 50, they noted an atypical manifestation of antibody-mediated rejection. A day 56 biopsy showed further evidence of antibody-mediated rejection, with no evidence of cellular rejection.
Doctors withdrew life support 60 days after the transplant, with the consent of the Bennett family, after determining there was irreversible injury to the xenograft. A later examination revealed that the heart weighed 600 grams, compared to 328 grams when transplanted.
“The pronounced sudden diastolic insufficiency and pathological global thickening of the myocardium without systolic dysfunction remain unexplained,” they said.
The authors also reported that they detected human herpesvirus 6, which cross-reacted with pCMV and was associated with allograft rejection.
To date, there have been six genetically engineered xenograft transplants in humans: the two recent NYU heart transplants, the Bennett heart transplant, and three kidney transplants in brain-dead patients (two at NYU one at the University of Alabama at Birmingham).
In theory, xenografts can make up for a national shortage of donor organs. Reyentovich said there are 6 million heart failure patients, 100,000 of whom are terminal, but only 3,500 heart transplants in the United States each year.
In an accompaniment NEJM editorial, Jeffrey L. Platt, MD, and Marilia Cascalho, MD, PhD, both of the University of Michigan at Ann Arbor, called for cautious optimism. “Given past failures, one might legitimately wonder whether this recent xenotransplantation [Bennett] provides insight into the future treatment of organ failure or simply responds to a long-standing quip that xenotransplantation is and always will be the future of transplantation,” they said.