Prenatal hemophilia A therapy shows maternal safety in sheep

An experimental prenatal cell and gene therapy designed to restore production of the missing clotting protein in hemophilia A showed maternal safety signs in a U.S. study in sheep.

The therapy, called PLC-mcoET3, is designed to transplant genetically engineered cells into the fetus so they can produce factor VIII (FVIII). Researchers found no evidence that treatment exposed the pregnant sheep to the transplanted cells or the clotting protein produced by the cells, a key safety question for prenatal treatments.

The results “suggest that the administration of PLC‐mcoET3 to the fetus during gestation does not result in detectable maternal exposure to the cells or gene products, attesting to the safety of this approach,” the researchers wrote.

The study, “Evaluation of Maternal Safety Following Prenatal Cell and Gene Therapy for Hemophilia A,” was published in Prenatal Diagnosis.

Recommended Reading

May 22, 2026 News by Lila Levinson, PhD

Real-world study backs safety of Hemlibra for acquired hemophilia A

Researchers explore treatment before birth

Hemophilia A is caused by mutations in the gene that provides instructions for making FVIII, a protein needed for blood to clot. A shortage of FVIII can lead to excessive and prolonged bleeding. Severe bleeding can begin early in life, sometimes soon after birth, which is why researchers are exploring whether treatment might one day begin before babies are born.

Experimental therapies include both cell and gene therapies aimed at restoring FVIII production before birth. Cell therapies involve transplanting the fetus with cells capable of producing FVIII, sometimes after they have been genetically engineered to do so. Gene therapies instead work by delivering a healthy version of the faulty gene to the body’s cells, typically with the aid of a modified viral vector, enabling them to produce functional FVIII.

However, prenatal treatment raises important safety questions. During pregnancy, small amounts of cells and genetic material can pass between fetal and maternal circulation through the placenta, meaning prenatal therapies could potentially expose pregnant patients to transplanted cells or newly produced FVIII and trigger immune reactions or other complications.

“Therefore, it is imperative to establish whether cells or gene therapy products are transferred across the placenta to the mother following prenatal therapy (PNT) and, if so, to determine the immune consequences of such transfer,” the researchers wrote.

To investigate this, a team of U.S. researchers tested the experimental prenatal therapy PLC-mcoET3 in pregnant sheep whose fetuses received treatment during gestation.

The therapy uses human placental cells, or PLCs, which are cells obtained from placental tissue and considered well-suited for transplantation. The cells were modified to carry genetic instructions for making mcoET3, a modified form of FVIII designed to improve clotting function.

The engineered cells were injected into the fetus’s abdominal cavity at 59–65 gestation days in sheep, roughly equivalent to 16–18 gestational weeks in humans.

Previous studies by the team showed that prenatal treatment with PLC-mcoET3 produced clinically meaningful and long-lasting FVIII activity, persisting for more than three years after treatment while reducing bleeding complications, without evidence of toxicity or immune responses against FVIII.

Sheep study focuses on maternal safety

In the current study, researchers focused instead on maternal safety, examining whether transplanted cells or their products reached the pregnant sheep, and whether this triggered immune responses.

No evidence emerged that the sheep had been exposed to the therapy. Neither transplanted PLCs engineered to produce mcoET3 nor the mcoET3 genetic material were detected in maternal blood, placental tissue, or umbilical cord samples.

Consistent with this, the sheep also showed no evidence of immune reactions against the transplanted cells. Immune cells collected during pregnancy and up to two years after birth did not react against either PLCs engineered to produce mcoET3 or the same cells before genetic modification.

This, however, did not mean the sheep’s immune systems were inactive. When exposed to unrelated human cells, their immune cells reacted normally, showing they retained the ability to recognize and respond to foreign material.

Blood samples collected during pregnancy and again one to two years after birth likewise showed no evidence that the sheep had developed antibodies against the transplanted cells.

Researchers also found no evidence of immune responses against the clotting protein produced by the transplanted cells. Blood tests found no antibodies against the engineered FVIII/ET3 protein nor evidence of memory T-cells targeting the protein, even months after birth. Memory T-cells are immune cells that remember specific foreign targets to help coordinate and sustain longer-lasting immune responses.

These studies attest to the maternal safety of prenatal treatment of hemophilia A with PLC‐mcoET3 by showing that its administration to the fetus “does not result in detectable maternal exposure to the cells or FVIII/ET3 protein,” the researchers concluded.