麻豆传媒

NATIONAL HARBOR, Md. -- Playing by the strict rules of the FDA, xenotransplant researchers are itching to apply the lessons learned from this year's historic case of cardiac surgery in their quest to move the transplant field forward amid a strained supply of donor organs.

In the landmark case, the first person to undergo a pig heart xenotransplant, David Bennett, age 57, had been denied a traditional human heart transplant from several programs before he ultimately agreed to the experimental surgery. The FDA green-lit the xenotransplant, and Bennett was kept alive for 60 days before succumbing to graft failure and sudden diastolic failure without evidence of traditional allograft rejection.

It remains unknown what caused Bennett to deteriorate to the point that life support was withdrawn.

"Whether this was rejection or not, we're still not sure," said Bennett's transplant surgeon, Bartley Griffith, MD, of the University of Maryland School of Medicine in Baltimore, speaking at a plenary session at the Heart Failure Society of America (HFSA) annual meeting.

Griffith's group speculates that the graft failure may have resulted from zoonosis, as Bennett tested positive for porcine cytomegalovirus (pCMV) DNA on day 20 after receiving the pig heart. The transplant team had tried to prevent this by having the pig undergo four recent PCR tests for pCMV, yet a dormant virus still dodged detection and was apparently reactivated when put inside the patient's body.

Another theory attributes the failure to pulling back on the antiviral ganciclovir when pCMV was confirmed. It remains to be seen whether continued ganciclovir could have stopped reactivation of any latent pCMV, according to Muhammad Mohiuddin, MBBS, head of the University of Maryland xenotransplant group, who was a panelist at the same plenary.

The plan is to move ahead cautiously even if Bennett's procedure "was considered a success by the family," according to Griffith.

In the search for the second xenotransplant candidate, the surgeon said he would not take someone as sick and bone marrow-insufficient as Bennett, and he's learned that pulling back on antivirals post-transplant is not a good idea. A good candidate might be someone who is elderly or has cancer, who can't take a ventricular assist device and has no other options, he suggested.

Ultimately, more human xenotransplants have to be performed for the sake of science, as the current non-human primate (NHP) cases are just not cutting it, Mohiuddin emphasized.

Major questions to be answered include how to better avoid pCMV infection, how to optimize the genetic engineering of pigs, and which antivirals and immunosuppressants work best for xenotransplant recipients.

"We need to convince the regulatory agencies the differences between NHPs and humans and have them give us permission to test out a few humans just like we did Mr. Bennett," Mohiuddin said, suggesting a provision for expanded access from the FDA.

"That's the major limitation," he told the room. "We are obligated to keep doing NHPs."

Even recent xenotransplants in brain-dead individuals are of limited scientific value, according to surgeon Christopher McGregor, MD, of the University of Minnesota in Minneapolis, speaking at a separate HFSA session.

He said it would take the community coming to a consensus on the preclinical criteria that must be met before xenotransplants move to clinical application. "Should the threshold be based on pig-to-NHP xenotransplants? How many animals? What level of survival and consistency?" he asked.

"All those challenges are clearly surmountable," McGregor added, predicting wider clinical application by the year 2026.

Ultimately, if developed successfully, xenotransplantation would open the door for a larger supply of hearts for advanced heart failure patients with few options.

Griffith suggested that one day, a physician might see a heart failure patient who isn't getting better with various therapies and be able to say, "How about a transplant and we'll schedule it for next Thursday?" The audience responded with light laughter.

Correction: The story was updated to clarify that pCMV DNA, not pCMV virus or viral infection, was detected in Bennett.

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