A team led by Children's Hospital Los Angeles has become the first in the world to demonstrate the possibility of using genetically engineered pig hearts as a potential "bridge" to heart transplant for critically ill babies.
The groundbreaking preclinical research could lead to a lifesaving alternative for supporting critically ill babies waiting for a new heart—particularly those with single-ventricle heart disease, most of whom currently die while waiting for a transplant.
John David Cleveland, MD , a congenital heart surgeon in the Heart Institute at Children's Hospital Los Angeles, led the study and presented the results April 28 in a plenary session at the International Society for Heart and Lung Transplantation Annual Meeting in Boston.
"The goal is to be able to use pig hearts instead of machines to support these babies until a suitable human heart can be found," Dr. Cleveland says. "We still need to do more research, but our studies show this is a viable model."
Xenotransplant has long been explored as a potential solution to the severe shortage of donor organs. Although ventricular assist devices (VADs)—mechanical pumps that help the heart circulate blood to the body—can support many patients during the long wait for a heart, infants with single-ventricle heart disease have a critical need for new options.
Currently, only about 30% of those babies will survive three months on a VAD, due to high rates of strokes, bleeding, and infections—meaning that few live long enough to receive a new heart.
"For those with single-ventricle disease, it's difficult to balance their circulations with a VAD—to find a way to give enough blood to the body and enough blood to the lungs," Dr. Cleveland explains. "A machine cannot constantly adapt to the physiology like an actual heart."
Xenotransplant could offer these babies a much better chance at surviving the time it takes to match with a suitable heart for transplant. "Not only could the outcomes be better, but a pig heart could potentially allow babies to go home while they wait for a human heart, as opposed to being connected to a VAD in the hospital," he adds.
A first-ever 'bridge'
The researchers began their studies five years ago, supported by an R33 Catalyze grant from the National Institutes of Health. So far, they have transplanted genetically modified pig hearts into 14 young, size-matched baboons at research facilities outside of California.
To date, eight of the 14 baboons have survived for several months with a pig heart. One of the baboons has so far lived for 620 days—nearly 21 months—the longest a nonhuman primate has ever lived with a pig heart. In addition, the team early on successfully reversed an episode of acute rejection in that baboon, the first time that's been done for a xenograft. That work was recently published in Xenotransplantation.
Importantly, the team also has become the first in the world to replace a functioning xenograft with a same-species heart. That was done in two of the baboons, with one living to 105 days.
"We have shown that replacing a xenograft with an allograft is feasible, which no one has done before," Dr. Cleveland says. "Based on those learnings, we are working to further modify and improve the protocol."
Harnessing new advances
He notes that science has come a long way since 1984, when "Baby Fae" received a baboon heart, becoming the first infant to receive a cardiac xenotransplant. She died 21 days later after her body rejected the heart.
One key advance is the ability to genetically modify organs to make them more humanlike. Immunosuppression technology is also far superior now, increasing the ability of the immune system to accept a xenograft.
The CHLA team is using an investigational medication called tegoprubart, an anti-CD40L antibody that aims to retrain the immune system to better accept a foreign organ as "self." The researchers' protocol also reduces the amount of time that the donor pig heart is out of circulation, which can help reduce the chances of rejection.
Through a partnership with eGenesis, a biotech company that specializes in xenotransplant, the researchers have also been using hearts from Yucatan miniature swine, a pig that grows more slowly than large white pigs.
Dr. Cleveland also says that xenotransplant may have a greater chance of success in babies than in older adults. In earlier studies, the team found that children younger than 18 do not have significant antibodies to pigs, while most adults do.
"The immature pediatric immune system is much more capable of accepting something completely foreign than the adult system is," he says. "We still have more research to do. But our hope is that we can eventually offer these babies a much better chance to live."
