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In utero therapy promising for preventing prenatal organ damage from rare genetic disease

Scientists found that treating the rare genetic disorder Pompe disease in utero may halt prenatal organ damage and improve health after birth. Pompe disease is caused by genetic changes that reduce the essential enzyme (a type of protein) acid alpha-glucosidase (GAA), and one form of the disease, called infantile-onset Pompe disease, leads to a near-complete lack of GAA. Because GAA is needed to break down glycogen, a form of sugar that fuels muscles, lack of GAA can cause glycogen buildup and irreversible organ damage, particularly to the muscles and heart. Fetal and newborn screening can diagnose infantile-onset Pompe disease, and prompt intravenous treatment after birth with GAA via an approach called enzyme-replacement therapy (ERT) can improve a child’s prognosis. However, improved treatments are needed, since ERT cannot reverse organ damage that occurred in utero, and some infants develop an immune response to ERT and die early in life.

Researchers tested whether treating Pompe disease earlier—via in utero ERT (IUERT) with GAA—could prevent prenatal organ damage and circumvent an immune response to the therapy. They teamed up with a family with a history of infantile-onset Pompe disease that was expecting a female child diagnosed with the disease. The researchers used ultrasonic imaging to guide delivery of six IUERT infusions into the umbilical cord, one every 2 weeks starting around 24 weeks gestation. This treatment was safe for mother and fetus. The infant continued to receive and tolerate ERT treatment after birth and was followed through 13 months of age. Her glycogen buildup levels significantly decreased following ERT, and unlike her siblings who had had Pompe disease, there were no signs of damage to her heart. In stark contrast to other children with this disease, she also displayed age-appropriate motor skills and muscle development, including appropriately meeting milestones such as crawling and walking. Though this report only covered one case, IUERT appears to have prevented the prenatal organ damage expected in infantile-onset Pompe disease, allowing the treated child to thrive through the first year of life. A larger clinical trial is in progress that will build on this remarkable result and provide more data about IUERT’s safety and efficacy at treating Pompe disease and other, related genetic diseases.

Cohen JL, Chakraborty P, Fung-Kee-Fung K,…MacKenzie TC. In utero enzyme-replacement therapy for infantile-onset Pompe's disease. N Engl J Med 387:2150-2158, 2022.

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