Prenatal surgery for spina bifida may get a boost from stem cells

For the first time, doctors have used stem cells to try and repair the spinal cords of human fetuses in the womb.

The new technique attempts to heal nerve damage caused by spina bifida, a disabling birth defect. In this condition, the bony tissue of a fetus’s spine doesn’t knit together properly around the spinal cord. That can cause a kaleidoscope of medical issues, including lifelong paralysis and bladder and bowel problems.

Traditional fetal surgery to patch up the spine can limit the scope of these problems — but it does not repair nerve damage that has already occurred. Adding living stem cells to the procedure might.

At least, that’s the goal of fetal surgeon Diana Farmer’s team. So far, the approach appears to be safe, the researchers reported earlier this year in theLancet. In six fetal patients with severe spina bifida, applying a stem cell–loaded patch to their exposed spinal cords 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 mends fetal spinal cords — remains unanswered. That’s because researchers are still performing follow-up assessments of the patients, who are now toddlers. At this stage, it’s too early to say how well the surgery worked, and Farmer is careful not to speculate. “If we could get every kid to not be in a wheelchair,” she says, “that would be fantastic.” But the team won’t know for a few years. Until then, Farmer says, 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 with the work. If the technique pans out, he says, it “could be a huge, important step in modern-day medicine.”

Maternal fetal medicine specialist Magdalena Sanz Cortes echoes the sentiment in a commentary that accompanied Farmer’s study. “We eagerly await follow-up results and definitive studies that might show benefit,” writes Sanz Cortes, of Baylor College of Medicine in Houston. “Such results would herald a new era in fetal surgery.”

First, doctors will need to better understand the procedure’s risks and benefits. 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 there’s room for improvement.

In the United States, roughly 1 in every 2,800 babies are born with spina bifida. This abnormality leaves the delicate spinal cord exposed in the womb. Without the bony protection of the vertebrae, the spinal cord can bulge through the back, making it especially vulnerable to injury. Like a chemical that burns, amniotic fluid washing over the open spinal cord can degrade 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 shunt surgically implanted in the days or weeks after birth for drainage. That can be lifesaving, but it’s also lifelong ­— a permanent implant that can malfunction or spur infection.

One way to avoid the shunt, and potentially some of the nerve damage accrued during pregnancy, is to surgically close the hole in the fetus’s spine in the womb. That was the conclusion of a landmark clinical trial 15 years ago that compared surgery done before and after birth. Prenatal surgery cut the need for shunts in half and doubled the chance of being able to walk without leg braces or other devices, Farmer’s team reported in the New England Journal of Medicine.

In utero repair is now the standard of care for severe spina bifida. But as well as it works, “there’s a lot of room for improvement,” Chmait says. Although kids who underwent prenatal surgery saw some gains in leg movement, most were still unable to walk.

 “That’s why we went back to the lab,” Farmer says.

Engineered stem cells might repair damaged tissue.

Farmer didn’t just want to close the spinal defect ­— she sought to fix the damage that had already been done. She thought stem cells might be the key. Scientists had already known that stem cells could renew themselves and repair tissues.Farmer hoped to tap into the cells’ regenerative powers to restore dying nerve cells. She brought the question to UC Davis bioengineer Aijun Wang’s lab. “How can we design a stem cell product to help neurons survive better?” he remembers her asking.

That kicked off a scientific odyssey that would span more than a decade and take the researchers from experiments in sheep and bulldogs, to finally, humans. Their work started with placental stem cells grown in a nutrient bath that Wang’s team engineered. The liquid prompts the cells to release a molecular concoction to protect neurons and stimulate their growth.

The researchers tested the stem cells in fetal sheep with a hole in their spine like those in babies with spina bifida. During the in utero repair surgery, doctors add hundreds of thousands of stem cells to a thin, flexible patch that looks like plastic wrap, Farmer says. Then, they use the patch to seal up the hole in the spine. The cells don’t stay forever. “We want them to get in there, do their job, deliver their magic stem cell juice, and repair that spinal cord,” Farmer says.

And that’s what the cells appeared to do. Sheep given the stem cell–impregnated patch tended to score better on tests of their ability to walk, stand and move their hind legs compared with those given the cell-free patch, the team reported in the Journal of Pediatric Surgery in 2021. The technique also helped restore most animals’ bladder and bowel function, Farmer and colleagues reported in a later study.

Other experiments in bulldogs born with spina bifida and treated after birth illustrate the stem cell patch’s promise, says Chmait. The dogs, Darla and Spanky, were able to walk, run and play just months after surgery, which he calls “remarkable.” Often, dogs with the condition cannot control their hind legs.

Farmer’s team is looking into how well such a postnatal approach might work. Could their technique one day help an adult who’s undergone a spinal cord injury, for instance? “We’re asking that question ourselves,” she says. Her team has started to investigate the idea in mice. 

Altogether, the team’s work in sheep and bulldogs has led to “significant, dramatic improvement,” says KuoJen Tsao, a pediatric surgeon at the University of Texas Health Science Center at Houston. And that has set the stage for the current trial in humans, which he calls exciting but “very, very preliminary.”

Farmer recognizes there’s much to do. “We’re not yet at a cure,” she says. Farmer is laser focused on one looming question. “How can we get the maximal 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 more patients, who researchers will monitor through age 6. They’ll track long-term safety data and evaluate efficacy — if kids see improvements in movement and have some over control their bladder and bowels. If the therapy works as well as it did in sheep, Farmer says, “we would be ecstatic.”

Chmait notes that the team’s surgical approach requires opening the mother’s uterus with an incision that’s larger than the ones used in most utero repair surgeries performed today, which may carry more risk for the mother. Farmer’s team used the technique so they could directly compare their data with that from the previous in utero repair trial, she says.

Chmait doesn’t currently work with stem cells himself, but if the trial’s outcomes look good, he says he’s ready to learn. Tsao agrees. He’s already thinking ahead to technical and logistical issues that may arise, like how to make the surgery available to anybody who needs it. Stem cell work can be a complicated process, he says, and not every facility is capable of producing the cell-imbued patch.

Tsao recognizes it will probably take years, and many more patients treated, before doctors have to address questions like that. But starting with a small group of patients, establishing safety and accumulating evidence over time is the norm for even potentially game-changing advances like this.

“That’s how most breakthroughs in medicine are,” he says.