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Surgeons at New York University (NYU) transplanted two genetically modified pig hearts into individuals who were brain dead, and saw good cardiac function, with no signs of immediate rejection during a 72-hour observation period.

The xenotransplants were conducted on June 16 and July 6 at NYU Langone Tisch Hospital in New York City, and had 10 aimed at preventing rejection and stopping abnormal organ growth.

Robert Montgomery, MD, PhD, of NYU Langone Health, was part of the surgical team, and said during a press briefing Tuesday that the procedure "had special significance for me." Montgomery is a .

"It was one of the most incredible things to see a pig heart pounding away and beating inside the chest of a human being," he said. "It is a great privilege for me to have witnessed that 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 by surgeons at the University of Maryland in Baltimore earlier this year, though the exact cause of the patient's death 60 days after the transplant in that case remains unclear.

Montgomery explained why studies would still need to be done in decedents when it's already been done in a human, (age 57). He said that, while the focus during a live xenotransplant would be on the patient and "keeping that individual alive and comfortable," conducting analyses in patients who are brain dead allows for a "much deeper analysis of what's occurring," including being able to conduct regular tissue sampling to better understand the immune response.

"In the transplant that occurred in Mr. Bennett, it was a tremendous feat to keep him alive for 2 months," Montgomery said. "But in the end, we don't know why that heart failed and why he died."

Montgomery said his team's next steps would be to assess xenograft viability for longer than 72 hours, and continue to engage with the FDA in the pre-IND (investigational new drug application) stage in order to eventually start phase I trials, which could be under way by 2025.

Also at the press briefing was Alice Michael, of Lawrence Kelly, age 72, one of the NYU recipients. Kelly was a Vietnam veteran who subsequently worked as a welder. She described him as someone who loved 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 he [Kelly] was in this research program and that he can help so many people," Michael said.

Knock-Outs and Knock-Ins

The pair of surgeries used pig hearts that had 10 genetic modifications, including four porcine gene knock-outs aimed at preventing rejection and abnormal organ growth, and six human transgenes, or knock-ins, to prevent rejection and other complications.

Montgomery said including the porcine growth hormone receptor knockout was key because observations made in primate transplant studies showed the pig heart continued to grow after transplant, meaning organs got too big for the primate's chest cavity and became compressed. He added that did appear to lead to the organs used in the current procedures being a bit undersized.

Surgical team member Nader Moazami, MD, NYU Langone surgical director of heart transplant, said the group had to make surgical modifications at the time of 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 some evidence that the amount of blood flow was not perfect enough," Moazami said.

He explained that the mismatch was mitigated in the second recipient (female, age 64) because she was smaller, and because the team had improved their adaptive surgical technique during the first procedure.

In both cases, heart function was "completely normal" on cardiac imaging during the 72-hour observation period, Moazami said.

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 detection assay in response to Bennett's case. While pCMV was not detected in Bennett's cells, it was detected in his blood, and seemed to be confined to the porcine heart. It had not been detected in pre-transplant screening.

The Bennett Experience

It's not clear exactly what went wrong in Bennett's transplant case; he developed an infection 43 days after transplant, and it was suspected the donor pig had a latent pCMV infection. According to a (NEJM) report, Bennett recovered from the infection, and was able to sit in a chair on day 48 post-transplant. But his status took a turn on day 49 and Bennett was put on extracorporeal membrane oxygenation (ECMO). It was the first time there was evidence of lowered cardiac output since the transplant, wrote Bartley P. Griffith, MD, of the University of Maryland, and colleagues.

While they reported that there was no evidence of rejection at day 50, they noted an atypical manifestation of antibody-mediated rejection. A biopsy on day 56 showed additional evidence of antibody-mediated rejection, with no evidence of cellular rejection.

Physicians withdrew life support 60 days post-transplant, with the Bennett family's consent, after determining there was irreversible injury to the xenograft. Subsequent examination revealed the heart weighed 600 grams, up from 328 grams at transplantation.

"The pronounced sudden diastolic failure and global pathologic myocardial thickening without systolic dysfunction remains unexplained," they stated.

The authors also reported that they detected human herpesvirus 6, which has been shown to cross-react with pCMV, and has been associated with allograft rejection.

To date, there have been six genetically modified xenograft transplantations into humans: the two recent NYU heart transplants, Bennett's heart transplant, and three kidney transplants in patients with brain death (two at NYU; one at the University of Alabama at Birmingham).

In theory, xenotransplants can make up for a national shortage in donor organs. Reyentovich said there are 6 million patients with heart failure, 100,000 of whom are in end-stage disease, yet only 3,500 heart transplants in the U.S. each year.

In an accompanying editorial, Jeffrey L. Platt, MD, and Marilia Cascalho, MD, PhD, both of the University of Michigan in Ann Arbor, urged cautious optimism. "Given past failures, one might justifiably ask whether this recent xenotransplantation [Bennett] provides a glimpse at the future treatment of organ failure or merely fulfills a longstanding quip that xenotransplantation is and always will be the future of transplantation," they stated.

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