In a medical first, researchers have delivered an enzyme into the womb to treat a fetus’ rare genetic disorder, helping head off heart and muscle defects. The girl, who cannot make the enzyme on her own, is now a seemingly healthy 16-month-old who has escaped the fate of two of her siblings. Both died from the same disease early in life.
This success paves the way for treating other genetic disorders in fetuses by infusing a needed enzyme through a pregnant person’s fetus’s umbilical vein, researchers conclude today in their report on the toddler in The New England Journal of Medicine (NEJM). It is “an essential proof-of-concept work” and “a cornerstone to better understanding … the benefit of enzyme therapy prenatally,” says Yin-Hsiu Chien, a medical geneticist at National Taiwan University Hospital who was not involved with the research.
The girl in this study, named Ayla, has Pompe disease, which results when a child inherits from both parents a defective gene for an enzyme that breaks down glycogen, a form of starch. The flawed gene results in low levels of the enzyme, called acid alpha-glucosidase (GAA), which allows glycogen to build up in muscle and cardiac cells, causing an enlarged heart and muscle weakness. Since 2006, the outlook for kids with Pompe has improved thanks to enzyme replacement therapy, which delivers infusions of a synthetic version of GAA every week or two starting at birth or after the disease is discovered. But with Ayla’s form of Pompe, called infantile-onset, no GAA is made and heart damage begins in utero, before enzyme replacement can begin.
Pediatric surgeon Tippi Mackenzie’s team at the University of California, San Francisco (UCSF), wondered whether simply infusing GAA into the umbilical vein could protect a fetus known to have Pompe. The procedure would resemble in utero blood transfusions, routinely given to fetuses with certain conditions. In utero enzyme replacement therapy seemed like “lower hanging fruit that had been overlooked,” Mackenzie says.
Providing the enzyme to a fetus might train its still-developing immune system to accept the synthetic protein rather than make antibodies that block it, as babies receiving GAA after birth often do. The enzyme should also reach the brain more readily, as the blood-brain barrier isn’t fully formed early in fetal development. That could help prevent the brain damage seen with some other disorders where the missing protein is needed by the central nervous system.
Two years ago, Mackenzie’s group tested the approach in mice with a disease similar to Pompe, which is part of a group called lysosomal storage diseases that lead to the buildup of harmful waste in cells. It worked, encouraging Mackenzie and collaborators to start a human trial. They enrolled a couple in Ottawa, Canada, who had two healthy children but lost two girls to infantile-onset Pompe, including one who died despite enzyme treatment from birth. When the mom, Sobia Qureshi, became pregnant again with Ayla, fetal testing revealed that she, too, had inherited two defective copies of the GAA gene from her parents and would have Pompe disease.
UCSF worked with Qureshi’s care team at the Ottawa Hospital and Children’s Hospital of Eastern Ontario to administer the enzyme six times starting at 24 weeks of pregnancy. When Ayla was born in June 2021, she showed no signs of the heart problems seen in infantile-onset Pompe, the researchers report in NEJM. Ayla continues to receive enzyme therapy and has developed normally, walking at 11.5 months.
Qureshi says in a video that having a healthy child with Pompe “is absolutely incredible” after losing two children to the disease. “She’s a miracle,” adds Alya’s father, Zahid Bashir.
As part of the same clinical trial, the researchers expect to try the in utero strategy on eight different lysosomal storage diseases, and they have already administered enzymes to two more fetuses. All of the participants will be closely followed after birth. Because the blood-brain barrier closes as children age, the enzyme therapy will eventually stop reaching their brains, which could lead to damage.
The researchers hope the in utero treatment will delay the onset of those problems until the children become eligible for treatments that could be permanent, such as a stem cell transplant or gene therapies in clinical trials, say Duke University School of Medicine medical geneticists and Pompe disease experts Priya Kishnani and Jennifer Cohen, who are collaborators on the trial and NEJM paper co-authors. “The hope is that if we can prevent neurologic damage starting in utero, we can halt progression and hopefully serve as a bridge,” they said by email.