With help from Duke doctors, a rare genetic disease is treated in the womb for the first time

For the first time, doctors started treating a fetus with Pompe disease, a rare and often fatal inherited condition, by infusing six courses of treatment directly into the umbilical cord.

Ayla Bashir, now 16 months old, seems to be faring better than babies who started treatment after birth.

The walls of Bashir’s heart, which Pompe disease typically makes thick and inefficient, appear normal in heart tests. She is walking, eating and growing normally, suggesting that the early treatment prevented the disease from causing irreversible damage to the baby’s muscles while in the uterus.

Bashir’s treatment, which involved doctors from Duke, University of Ottowa and University of California San Fransisco, was described in the New England Journal of Medicine Wednesday.

Dr. Priya Kishnani, a leading Pompe researcher from Duke and author of the paper, is still cautiously optimistic about the treatment’s success. It’s too soon to tell whether the treatment will significantly change the course of her illness.

For children who start therapy shortly after birth, the two-year mark is typically the “tipping point,” when doctors start to see motor impairments.

“I never like to give false hope to parents,” Kishnani said. “At this time baby Ayla looks terrific and like any typically developing baby at this age, however, we have got to continue to monitor her very closely to see if, as she gets older, the disease is going to catch up with her.”

Playing catch-up

If left untreated, most babies with infantile Pompe disease die before they turn 2 from cardiac or respiratory complications.

A gene mutation prevents the body from making an enzyme called GAA, which breaks down a type of sugar called glycogen.

Without that crucial enzyme, glycogen starts to build up in the body’s cells, causing a myriad of problems. Babies with the disease tend to have muscle weakness (sometimes referred to as “floppy baby syndrome”), a “grossly enlarged heart” and feeding problems.

Enzyme replacement therapy, during which patients receive weekly infusions of the enzymes they are missing, can extend their lives by many years (the oldest survivor of infantile Pompe disease is currently 23). Myozyme, created by Duke researchers, is the first and only FDA-approved therapy for infantile Pompe disease.

The issue, Kishnani said, is that irreversible damage begins in the uterus.

“You’re playing catch-up when a baby is born,” she said.

Zara, Ayla’s older sister who was also diagnosed with Pompe, already showed signs of muscle damage at birth. Despite starting ERT treatment at six and a half months old, Zara succumbed to the disease at about two and a half years old.

Is it worth it?

The fetal treatment, while a first in many regards, will likely benefit a very small number of patients.

The severe type of Pompe disease that afflicts Ayla is incredibly rare, affecting about one in 138,000 babies.

Most children with Pompe disease aren’t diagnosed until after they’re born during newborn screening tests. North Carolina is expected to add Pompe disease to its list of newborn screening tests this month.

If a family happens to know they are a carrier of the genetic mutation and find the disease during a prenatal test, they also might choose to abort the baby.

Dr. Barry Byrne, a rare disease researcher and pediatric cardiologist at the University of Florida who was not involved in the case study, said he wonders whether treatment is worth the outcome.

He said it’s not clear from the study whether the fetal treatment will leave Ayla significantly better off than if she had started ERT immediately after birth.

“It’s one of those circumstances where even though it’s technically feasible to do lots of different fetal interventions, they carry some risk,” he said. “I think in the long run there, they will be faced with the same challenges as other infants treated in the newborn period.”

Ayla will still have to undergo weekly enzyme replacement therapy treatments, which can cost hundreds of thousands of dollars a year for adults. As she gets older and glycogen begins building up in her brain, the treatment won’t be able to bypass the blood-brain barrier to clear it out, Byrne said.

Still, Kishnani said the case study provides some hope to families with stories similar to Ayla’s.

She also hopes that if new gene therapies are approved for Pompe disease, the fetal treatment could prevent muscle damage in the uterus until they are born.

“There are many firsts here,” Kishnani said. “There is a whole class of diseases that could benefit from this.”

Teddy Rosenbluth covers science and healthcare for The News & Observer in a position funded by Duke Health and the Burroughs Wellcome Fund. The N&O maintains full editorial control of the work.