The combination of placenta-derived stem cells (PMSCs) with standard in utero repair for severe spina bifida appears feasible and safe, with no cell-related adverse events observed at birth, a first-in-human study showed.

In the phase 1 trial involving six fetuses with myelomeningocele, the most common and most severe type of spina bifida, investigators successfully delivered a live cellular therapy directly to the exposed fetal spinal cord during standard open fetal surgery. All infants were born with intact repair sites and had no cerebrospinal fluid (CSF) leak, infection, wound dehiscence, or abnormal tissue growth.

The therapy did not interfere with standard surgical workflow or immediate neonatal outcomes and met prespecified safety thresholds for the trial to continue.

“Applying a biologically living stem cell therapy to try to improve the clinical outcomes (the paralysis and bowel and bladder dysfunction) for children with spina bifida is safe, and we are proceeding with further testing of this novel therapy,” lead investigator Diana L. Farmer, MD, distinguished professor and chair, Department of Surgery, UC Davis Children’s Hospital, University of California Davis Health, Sacramento, California, told Medscape Medical News.

The study was published online on February 26 in The Lancet.

The Two-Hit Hypothesis

The “two-hit” hypothesis suggests that neurologic disability comes not only from abnormal spinal cord development in early gestation but also from progressive injury to exposed neural tissue during pregnancy. Although standard in utero repair prevents further damage, it cannot reverse existing injury.

Preclinical studies have shown that mesenchymal stem cells may provide neuroprotective and anti-inflammatory effects, which could potentially preserve spinal cord tissue during this critical window of fetal development. In animal models, placenta-derived mesenchymal stem cells improved motor outcomes compared with surgery alone.

Until now, no human trials had evaluated the safety of stem cell delivery to the fetal central nervous system due to concerns about tissue overgrowth, wound healing, and maternal or fetal complications.

“More and more centers across the United States are offering prenatal surgery for myelomeningocele. Our trial is unique in that our primary objective is to improve motor function for children with spina bifida,” study author Aijun Wang, PhD, Chancellor’s Fellow Professor of Surgery and Biomedical Engineering and co-director of the Center for Surgical Bioengineering, UC Davis Health told Medscape Medical News.

In the Cellular Therapy for In Utero Repair of Myelomeningocele (CuRe) trial, a phase 1, single-arm study, investigators evaluated the feasibility and safety of PMSCs seeded onto an FDA-approved extracellular matrix (ECM) and applied topically to the exposed fetal spinal cord during prenatal repair of myelomeningocele.

Six pregnant patients carrying fetuses diagnosed with the disorder were enrolled between June 2021 and December 2022.

In the study, eligible fetuses were between 19 and 26 weeks’ gestation, had lesion levels ranging from T1 to S1, demonstrated hindbrain herniation on MRI, and had a normal karyotype. All participants in this initial cohort were White and non-Hispanic individuals, with a median maternal age of 27.5 years.

During standard open fetal surgery, investigators applied a single dose of the cell-seeded ECM graft directly to the exposed spinal cord, followed by dural and skin closure.

The cells were derived from donated placentas, tested for identity and sterility, and applied at a density of 300,000 cells per square centimeter.

The primary endpoints were feasibility of delivery and early safety, including wound healing, infection, CSF leak, abnormal tissue or tumor formation, and perinatal death. Outcomes were assessed at birth and during neonatal hospitalization.

Promising Early Results

All six fetal surgeries were successful and the stem cell-seeded graft was applied without technical complications. Gestational age at surgery ranged from approximately 24-26 weeks, and the infants were delivered by cesarean section at a median gestational age of approximately 35 weeks.

At birth, all infants had intact repair sites with no evidence of CSF leak, infection, wound dehiscence, or abnormal tissue growth. Once the newborns were clinically stable, postnatal MRI showed the reversal of hindbrain herniation in all cases. None required CSF shunting for hydrocephalus, and all were discharged without home oxygen. The investigators did not find any tumors or unexpected tissue proliferation.

Although several infants were born preterm, neonatal outcomes were consistent with historical prenatal repair data. The study was not powered to assess efficacy and did not include formal motor function outcomes. The absence of cell-related adverse events met prespecified safety thresholds and allowed the trial to proceed to a larger phase 1/2a study enrolling additional patients.

Toward Functional Independence

The investigators noted that the therapy was designed to seamlessly complement existing prenatal surgical workflows rather than replace standard repair.

“We have shown that our stem cell product is a feasible and safe adjunct to prenatal treatment,” Wang said. “Our technology can integrate into standard surgical workflow, providing regenerative benefits without compromising wound healing or interfering with reversal of hindbrain herniation.”

As the trial expands into a phase 1/2a study with increased enrollment, long-term safety monitoring remains a priority.

“While we are encouraged, though not surprised, based on our preclinical studies, by our safety results thus far, we carefully monitor each patient until at least age 6 and remain vigilant for any stem-cell-related complications,” Wang noted.

“We will continue to monitor for any unexpected long-term risks of stem cells,” Farmer added.

The investigators concluded that intervention during fetal development offers the best opportunity to preserve neurologic function.

“Our goal is to improve motor function beyond what can be achieved with surgery alone,” Wang said. “The first and most important step was showing that the stem cells were safe. And so far, we have done that.”

Wang emphasized that the greatest potential impact of this therapy lies in preserving motor neurons and improving the chances of independent walking.

“Although functional outcomes are still under study, the goal is to intervene during a critical window of fetal development to reduce lifelong disability and meaningfully improve functional independence,” he added.

The ultimate goal is to achieve meaningful improvement beyond standard fetal surgery — ideally enough to enable all children to avoid lifelong wheelchair dependence and potentially improve bowel and bladder function, consistent with findings from preclinical studies, Farmer said.

From Neuroprotective to Neurodegenerative

Commenting for Medscape Medical News, Jan Deprest, MD, PhD, professor of obstetrics and gynecology, University Hospitals Leuven and KU Leuven, Leuven, Belgium, acknowledged that persistent functional limitations are seen during standard fetal surgery and this trial aimed to address just that with the addition of fetal stem cell therapy.

“The strategy trialed here tries to address the above challenge by modifying the surgical repair, enriching the coverage with stem cells,” said Deprest, who is a European leader in fetal therapy research. Based on extensive experimental work, “stem-cell-enriched scaffolds are likely to improve wound healing and potentially also nerve function recovery, at the level of the spinal defect.”

While preclinical models remain imperfect, animal defects “never mimic completely the embryonic malformation present in nature,” Deprest said, adding that moving to humans provides initial insight onpotential functional benefits alongside the primary goal of safety and feasibility.

With these outcomes now demonstrated, Deprest said the approach “certainly reports outcomes at least comparable with what one can expect based on current prenatal procedures,” using the MOMS trial as a benchmark for evaluating reversal of hindbrain herniation, wound closure at birth, early diversion surgery, and prematurity.

“Some critics will (rightfully) say that the MOMS trial outcomes are no longer a benchmark, as surgery and experience have improved, but it is the only unbiased data we have,” he acknowledged.

The study was by no means designed nor powered to demonstrate efficacy, Deprest said.

The central finding is that placing allogeneic cells directly onto the fetal spinal cord appears to be safe, with no early evidence of inflammation, abnormal tissue growth, or impaired wound healing, Deprest added.

Looking ahead, he said future studies will evaluate whether this approach can reduce neuroinflammation and apoptosis while promoting structural and functional preservation — or even recovery — potentially shifting fetal repair from a primarily neuroprotective strategy to a neuroregenerative one.

This study was funded by the California Institute for Regenerative Medicine and Shriners Children’s. Farmer and Wang reported the following patents assigned to the Regents of the University of California, Davis: US patent numbers 10058572, 11583557, and US patent application 18/098631. Deprest reported having no relevant financial relationships.