For the first time, doctors have used stem cells to try to repair the spinal cords of human fetuses in the womb.
The new technique attempts to cure nerve damage caused by spina bifida, a crippling birth defect. In this condition, the bone tissue in the fetal spine does not knit properly around the spinal cord. This can lead to a kaleidoscope of medical problems, including permanent paralysis and bladder and bowel problems.
Traditional fetal surgery to repair the spine can limit the extent of these problems, but it does not repair nerve damage that has already occurred. Adding live stem cells to the procedure could do that.
At least that’s the goal of fetal surgeon Diana Farmer’s team. So far, the approach appears safe, the researchers reported earlier this year in theLancet. In six fetal patients with severe spina bifida, apply a patch loaded with stem cells to their exposed spinal cord did not cause infection, tumor growth, or interfere with healing. That’s important because “no one knew what stem cells would do inside a fetus,” says Farmer, of the University of California, Davis.
For now, the vital question – whether the technique repairs the fetal spinal cord – remains unanswered. Indeed, researchers are still conducting follow-up assessments of patients, who are now toddlers. At this point, it’s too early to say how well the operation has worked, and Farmer is careful not to speculate. “If we could get all the kids out of wheelchairs,” she says, “that would be fantastic.” But the team won’t know for a few years. Until then, Farmer said, she doesn’t want to give people false hope.
In some ways, this study represents “a seismic shift” in the field, says Ramen Chmait, director of Los Angeles fetal surgery at the University of Southern California, who was not involved in the work. If the technique succeeds, he says, it “could be a huge and important step in modern medicine.”
Maternal-fetal medicine specialist Magdalena Sanz Cortes echoes this sentiment in a commentary accompanying Farmer’s study. “We look forward to follow-up results and definitive studies that may show benefit,” writes Sanz Cortes, of Baylor College of Medicine in Houston. “Such results announce a new era in fetal surgery.
First, doctors will need to better understand the risks and benefits of the procedure. At this point, Chmait says, Farmer’s team has taken “the first step of a marathon.”
Spina bifida can be repaired in the womb, but improvements are possible.
In the United States, approximately 1 in 2,800 babies are born with spina bifida. This abnormality leaves the delicate spinal cord exposed in the uterus. Without the bony protection of the vertebrae, the spinal cord can bulge in the back, making it particularly vulnerable to injury. Like a burning chemical, amniotic fluid flowing over the open spinal cord can damage it. And as the baby grows, it rubs against the walls of the uterus, damaging unprotected nerve cells.
Beyond paralysis and other serious problems, this damage can cause fluid to build up in the brain. Some babies require a surgically implanted shunt within days or weeks of birth for drainage. It can save lives, but it’s also permanent: a permanent implant that can malfunction or cause infection.
One way to avoid the shunt, and potentially some nerve damage accumulated during pregnancy, is to surgically close the hole in the fetus’s spine in the womb. This was the conclusion of a landmark clinical trial 15 years ago that comparison of surgical procedures performed before and after birth. Prenatal surgery has cut the need for shunts in half and doubled the chances of being able to walk without leg orthoses or other devicesFarmer’s team reported in the New England Journal of Medicine.
In utero repair is now the standard of care for severe spina bifida. But even if it works, “there’s still a lot to do,” Chmait says. Although children who had prenatal surgery saw some progress in leg movements, most were still unable to walk.
“That’s why we went back to the lab,” says Farmer.
Artificial stem cells could repair damaged tissues.
Farmer didn’t just want to fix the spinal defect – she sought to repair the damage already done. She thought stem cells might be the key. Scientists already knew that stem cells could renew themselves and repair tissues. Farmer hoped to harness the regenerative powers of cells to restore dying nerve cells. She posed the question to the lab of UC Davis bioengineer Aijun Wang. “How can we design a stem cell product to help neurons survive better? he remembers her asking.
It kicked off a scientific odyssey that would span more than a decade and take researchers from experiments on sheep and bulldogs to humans. Their work began with placental stem cells grown in a nutrient bath designed by Wang’s team. The liquid tricks cells into releasing a molecular concoction to protect neurons and stimulate their growth.
Researchers tested stem cells from fetal sheep with a hole in their spine, like those from babies with spina bifida. During in utero repair surgery, doctors add hundreds of thousands of stem cells to a thin, flexible patch that resembles plastic wrap, Farmer says. Then they use the patch to plug the hole in the spine. Cells don’t stay around forever. “We want them to go in there, do their job, deliver their magic stem cell juice and repair that spinal cord,” Farmer says.
And that’s what the cells seemed to be doing. The sheep that received the patch impregnated with stem cells tended to perform better on tests of their ability to walkstand and move their hind legs compared to those who received the acellular patch, the team reported in the Journal of Pediatric Surgery in 2021. The technique also helped restore bladder and bowel function in most animalsFarmer and colleagues reported in a later study.
Other experiments on bulldogs born with spina bifida and treated after birth illustrate the promise of the stem cell patch, Chmait says. The dogs, Darla and Spanky, were able to walk, run and play just months after the surgery, which he calls “remarkable.” Often, dogs with this condition cannot control their hind legs.
Farmer’s team is studying how well such a postnatal approach might work. Could their technique one day help an adult with a spinal cord injury, for example? “We ask ourselves this question,” she says. His team began studying this idea in mice.
Overall, the team’s work on sheep and bulldogs led to “a significant and dramatic improvement,” says KuoJen Tsao, a pediatric surgeon at the University of Texas Health Science Center at Houston. And that paved the way for the ongoing human trial, which he calls exciting but “very, very preliminary.”
Farmer acknowledges that there is much to be done. “We haven’t found a cure yet,” she says. The farmer is laser-focused on a looming issue. “How can we achieve maximum improvement in spinal cord function?” » she asks. “We will not give up.”
Scientists are waiting to see how well the stem cell patch worked.
Now, Farmer’s team is expanding the trial to include 35 additional patients, whom researchers will monitor until they are 6 years old. They will track long-term safety data and assess effectiveness – whether children see improvements in their movements and gain control of their bladder and bowels. If the therapy works as well as it does in sheep, Farmer says, “we would be thrilled.”
Chmait notes that the team’s surgical approach requires opening the mother’s uterus with a larger incision than those used in most uterine repair surgeries performed today, which may carry more risk for the mother. Farmer’s team used this technique so they could directly compare their data with that of the previous in utero repair trial, she says.
Chmait isn’t currently working with stem cells himself, but if the results of the trial look good, he says he’s willing to learn. Tsao agrees. He is already thinking about technical and logistical problems that might arise, such as how to make the surgery accessible to everyone who needs it. Stem cell work can be a complicated process, he says, and not all facilities are capable of producing the cell-infused patch.
Tsao acknowledges that it will likely take years, and many more patients treated, before doctors face such questions. But starting with a small group of patients, establishing safety, and accumulating evidence over time is the standard for potentially revolutionary advances like this.
“This is how most breakthroughs in medicine happen,” he says.