The symptoms of a rare hereditary condition are prevented by enzyme therapy given directly to the fetus.


Researchers have successfully administered an enzyme into the womb to cure a fetus’ uncommon genetic disease, preventing the development of heart and muscle problems in a medical first. The daughter, unable to produce the enzyme on her own, is now a 16-month-old who appears to be in good health and has avoided the tragedy of two siblings. Early deaths from the same illness claimed both of them.

Researchers conclude today in their article on the kid in The New England Journal of Medicine that this might open the way for curing additional genetic diseases in babies by injecting a necessary enzyme through a pregnant person’s umbilical vein (NEJM). According to Yin-Hsiu Chien, a medical geneticist at National Taiwan University Hospital who was not involved in the study, it is “a vital proof-of-concept effort” and “a cornerstone to a better understanding… the usefulness of enzyme therapy prenatally.”

Ayla, the study participant’s daughter, has Pompe disease, which develops when a kid inherits from both parents a faulty gene for an enzyme that breaks down glycogen, a type of starch. Low levels of the acid alpha-glucosidase (GAA) enzyme, caused by the defective gene, lead to glycogen buildup in muscle and cardiac cells, resulting in an enlarged heart and muscle weakness. Since 2006, enzyme replacement treatment, which administers infusions of a synthetic form of GAA starting at birth or after the condition is identified, has improved the prognosis for children with Pompe. However, no GAA is produced in Ayla’s kind of Pompe, known as infantile-onset, and cardiac damage starts even before the enzyme replacement.


The University of California, San Francisco (UCSF) team led by pediatric surgeon Tippi Mackenzie questioned whether injecting GAA into a pregnant woman’s umbilical vein would be sufficient to protect a fetus with Pompe disease. The process would imitate the routine blood transfusions given to fetuses with particular disorders in gestation. According to Mackenzie, in utero, enzyme replacement therapy appeared to be “lower hanging fruit that had been neglected.”

By giving the enzyme to a fetus, one can prevent the immune system from producing antibodies that block the synthesized protein, as they frequently do in newborns who get GAA. Due to the incomplete formation of the blood-brain barrier early in fetal development, the enzyme should also be able to reach the brain more easily. That may aid in preventing the brain damage seen in some other illnesses when the central nervous system requires the missing protein.

Two years ago, Mackenzie’s team tested the strategy in mice with Pompe-like disease, which is a subset of lysosomal storage diseases that cause dangerous waste to accumulate in cells. It successfully inspired Mackenzie and her colleagues to begin a human experiment. They included a Canadian couple from Ottawa who had two healthy kids but lost two girls to infantile-onset Pompe, including one who passed away despite enzyme treatment from birth. Fetal tests revealed that Ayla would also inherit two faulty copies of the GAA gene from her parents and would have Pompe disease when the mother, Sobia Qureshi, became pregnant again.
Beginning at 24 weeks of pregnancy, UCSF collaborated with Qureshi’s medical staff at the Ottawa Hospital and Children’s Hospital of Eastern Ontario to deliver the enzyme six times. According to the researchers’ NEJM report, when Ayla was born in June 2021, she had no heart issues associated with infantile-onset Pompe. Ayla is still receiving enzyme therapy, and at 11.5 months, she was walking properly.


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