Hearts taken from pigs engineered so the organs won’t produce extreme immune reactions if transplanted into humans or other primates can support the life of recipient baboons for up to 195 days, according to a report in Nature today (December 5). The study, in which four baboons lived in good health for several months after surgery, brings xenotransplantation one step closer to the clinic, say researchers.
“I think this is an extremely important paper. It provides the longest survival yet of orthotopic heart [transplants] across the species barrier of pig to primate,” says transplantation specialist David Sachs of Columbia University Medical Center in New York who was not involved in the research. “Six months is a major jump forward.”
“With the survivorship that they’ve seen . . . there’s every reason to think that progression into the clinic is a worthwhile thing to do,” adds xenotransplantation researcher Guerard Byrne of the University of Alabama at Birmingham who also did not participate in the study.
Heart failure claims the lives of hundreds of thousands of people in the US every year. While there are medications to manage the symptoms—such as those for reducing blood pressure—the only current cure is to receive a new donor heart. Unfortunately, demand vastly outstrips supply. “There are many patients who would benefit from a transplant, but who are never going to get one,” says Byrne. These are the people who might one day benefit from xenotransplantation, he suggests.
To this end, researchers have looked to pigs as potential donor species, genetically engineering them to remove their most immunogenic antigens. But, so far, when the pigs’ organs have been transplanted into primates and the recipients take immunosuppressive drugs, the maximum survival of a baboon has been 57 days. That animal finally succumbed to an antibody-mediated rejection of the organ, explains Byrne, who was involved with this past research.
The development of novel immunosuppression approaches—including the use of anti-CD40 antibodies, which tamp down a variety of immune and inflammatory responses—have since enabled pig hearts to survive in baboons for two and a half years, but only in a nonfunctional capacity (the baboons retained their own hearts), explains cardiothoracic surgeon Keith Horvath of the Association of American Medical Colleges in Washington, DC, who carried out this earlier work at the National Institutes of Health, but was not part of the current study.
Now, Bruno Reichart of the University of Munich and colleagues have adopted this new immunosuppression method and optimized aspects of the xenotransplantation procedure to carry out pig-to-baboon heart replacements that support the recipients’ lives for longer. In particular, they improved the preservation of the donor heart and restricted heart growth within the primates. Pigs are much larger than baboons and because these organs came from juvenile pigs, the hearts grew accordingly. To stop this, the team both reduced the baboons’ blood pressure to avoid enlargement and gave the animals a drug called temsirolimus, which prevents the proliferation and growth of cells.
Of the five baboons that underwent this optimized technique, one had thoracic lymph node blockage causing fluid on the lung and had to be euthanized at 51 days, two were euthanized after three months of good health—the expected endpoint of the study—and two were euthanized after six months, following an extension of the study. Removal of the temsirolimus treatment shortly before the termination of the study caused the hearts of both animals to grow larger, highlighting the importance of this treatment in the baboon model.
But in patients, heart growth may not be an issue. Because adult humans are a closer size-match to pigs and because smaller pigs could be used as donors if necessary, says Sachs, the procedure may actually work better in humans than in baboons.
“I’m not saying that we’re ready to go into the clinic tomorrow,” says Byrne, but “the field can be stuck optimizing for nonhuman primates and get nowhere, when what we really need to do is to begin optimizing in humans.”
M. Längin et al., “Consistent success in life-supporting porcine cardiac xenotransplantation,” Nature, doi:10.1038/s41586-018-0765-z, 2018.