In a first, a fatal enzyme deficiency is treated in the womb

To protect this child from the same genetic disease that killed two older siblings, treating her as soon as she was born might only work so well, the doctors knew. So they dialed back the therapeutic clock, delivering the medication to her as a fetus.

Now 16 months old, Ayla appears totally healthy. She still requires weekly doses of the medication, an enzyme that she can’t produce on her own, but she has no symptoms of the condition she inherited, the most serious form of the rare Pompe disease. Her heart is strong, and she started walking at a typical 11 months old.

Ayla’s case, described Wednesday in the New England Journal of Medicine, was the first in which doctors provided this type of treatment — called enzyme replacement therapy, or ERT — in utero. To help a family the disease had already marked with tragedy, experts at multiple institutions across borders had to overcome both a narrow window to provide care as well as Covid-19 travel barriers.

More broadly, the success of Ayla’s case serves as further proof of concept that treating genetic diseases in fetuses may be able to stave off the damage that would otherwise accrue even before the baby was born. In that way, it provides a jolt as researchers explore the possibility of one day trying gene therapy or even genome editing in utero.

The case is “expanding the repertoire of fetal therapy,” said Tippi MacKenzie, a pediatric and fetal surgeon at University of California, San Francisco, and one of the experts involved in Ayla’s care.

Pompe disease belongs to a group of so-called lysosomal storage disorders, which cause the buildup of toxic junk in cells. Patients with Pompe in particular have trouble producing an enzyme called GAA, without which a sugar called glycogen accumulates and damages the heart and other muscles. Diseases like Pompe are treated by giving patients the enzyme they can’t make (hence the name enzyme replacement therapy), sometimes in combination with other medicines.

Children with the most severe type, an infantile form of Pompe that affects fewer than 1 in 100,000 babies, are often already born with damage to the heart muscle that makes it harder for the organ to pump. They have progressive muscle weakness — doctors describe them as “floppy” babies — and without treatment, they typically die within two years.

It was in January 2021 that a genetic analysis showed that this family’s latest pregnancy was positive for Pompe. An older child had been diagnosed at 5 months, started treatment, and died at 29 months. A second sibling was diagnosed prenatally, received palliative care after birth, and died at 8 months from cardiorespiratory failure. (The family has two other children not affected by the disease, which is caused when a child inherits a faulty copy of the GAA gene from each parent.)

Pranesh Chakraborty, a physician at CHEO, a children’s hospital in Ottawa, who specializes in inherited metabolic disorders, has been seeing the family since the first sibling was diagnosed with Pompe. With the results of the genetic test in the new pregnancy, he needed to come up with a treatment plan. Past research has shown that initiating ERT right at birth is helpful, but that it can’t fully prevent the onset of the disease. Ultrasounds, for example, showed that the second sibling who died was already showing signs of cardiomyopathy — a heart condition that’s a telltale symptom of Pompe — while in the womb.

Looking for help, Chakraborty shot a note to someone he has known for years: Priya Kishnani, the chief of medical genetics at Duke and a leading Pompe expert. What was the latest on Pompe?

“Whenever you’re looking for what’s new and what’s going on in any specific rare disease, you both go to the literature, but you go to your colleagues,” Chakraborty said.

It turned out that a year earlier, Kishnani’s Duke colleague, Jennifer Cohen, who also specializes in pediatric medical genetics, had been collaborating with MacKenzie and her team at UCSF. MacKenzie had been putting together a protocol for a clinical trial for delivering ERT to fetuses affected by different lysosomal storage disorders.

The doctors from the various institutions started talking, and realized that this fetus might make a good candidate for the trial at UCSF. That’s when Covid got in the way.

Travel restrictions and quarantine requirements made it infeasible for the family to travel back and forth from Ottawa to San Francisco. So MacKenzie shared the trial protocol with the Canadian team, outlining the nitty-gritty of everything from calculating the right dose of the drug for a fetus to the paperwork used to get regulatory clearance for the trial. The Canadian team adapted the information to get ethics clearance for the treatment.

“All of it had to move very rapidly,” MacKenzie said.

Then, on March 24, 2021, maternal-fetal medicine specialists at the Ottawa Hospital delivered the first dose of the enzyme therapy, injecting it into the umbilical vein to reach the fetus. All told, there were six prenatal infusions.

In a way, the strategy relied on two well-established interventions. If a fetus has anemia, for example, doctors can provide a blood transfusion through the same umbilical vein route. And the drug they were using, alglucosidase alfa, is an approved medicine for treating infantile-onset Pompe. The novelty in this case was the combination of method and medication.

The infusions proved to be safe for both mom and baby, and Ayla was born at term that June with no signs that the mutations she had inherited had started to weaken her heart or any other muscles. She’s met developmental milestones and doesn’t show any loss of motor function. Biomarkers that can be used as signals for treatment response and disease progression are also in typical ranges.

“Our results are consistent with in utero ERT attenuating or even halting the disease process in the fetal period,” the doctors wrote in their case report. “Furthermore, although it is accepted that starting treatment as early as possible improves outcomes in patients with lysosomal storage diseases … our results suggest that moving the window for therapeutic intervention into the prenatal period may further improve postnatal outcomes.”

The doctors cautioned that while Ayla seems healthy, she still receives a dose of ERT every week, and will be monitored for disease progression.

The in utero treatment “didn’t eliminate the need for continued postnatal therapy, but it prevented any cardiomyopathy” thus far, Cohen said. “We’re hopeful that this trajectory will continue.”

Kishnani, speaking on a joint video call with her Duke colleague, echoed that: “It’s not like we’re saying, ‘Hey, this is a checked box and a success story.’ It is looking very promising, but I still think we’re going to follow this child very carefully.”

How widely such a procedure can be offered for now is also an open question. MacKenzie stressed the ongoing clinical trial is crucial to establish the risks and benefits of in utero ERT, something an individual case report can’t do.

Most kids born with diseases like Pompe also aren’t diagnosed as fetal patients. In this case, doctors only knew to test for Pompe during pregnancy because of the family’s history. Many children are only diagnosed with Pompe after showing symptoms. The disease is included in the suite of genetic conditions that all U.S. newborns are tested for in just over 30 states, according to Kishnani.

But based on Ayla’s family history, the medical team also knew that her disease would likely progress quickly.

“One difficulty facing this approach is that it is hard to obtain an early genetic diagnosis, and in many diseases, a genetic diagnosis isn’t necessarily predictive of the progression of the disease,” Simon Waddington, a professor of gene therapy at University College London, who was not involved with Ayla’s case, wrote in an email. “However in this case, the authors correctly point out that there were two previous siblings, so the prognosis for this fetal patient was well known.”

Still, Waddington called the case report “pretty exciting.”

“It is another example of fetal therapy for an inherited genetic disease, where treating as early as possible in life may have substantial benefits,” he wrote in the email.

Karen Fung-Kee-Fung, a maternal-fetal medicine specialist at the Ottawa Hospital, who took care of Ayla’s mother’s pregnancy, said the case could provide a boost for other families who’ve had children with diseases like Pompe.

“For those whose lives have been impacted already by a child who has special-care needs, it affects a family forever, and it affects how they come together as a family, it affects the other children who may not have the disease,” Fung-Kee-Fung said. “It’s the hope for other families, isn’t it?”

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