For the first time, a child with a rare genetic disease was treated and cured before birth

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For the first time, a team of doctors has cured a baby with Pompe disease by intervening before the baby is born. Two sisters of the deceased child also suffered from this rare genetic disease, which led to severe cardiomyopathy. The 16-month-old girl is doing well and is currently developing normally.

Pompe disease (or glycogen storage disease type 2) is a genetic disease that results in a deficiency of acid alpha-glucosidase (GAA) or acid maltase, an enzyme that allows the breakdown and processing of glycogen, the form in which cells store sugars. This disease causes a variety of symptoms (progressive muscle weakness, difficulty breathing, etc.) that vary depending on the age of the patient at the onset of the disease. The infantile form, which usually appears before the age of one, is accompanied by severe heart problems; therefore it is especially serious.

If untreated, the lack of acid alpha-glucosidase – almost total in the infantile form of the disease – leads to the accumulation of glycogen in lysosomes, then in the cytoplasm of cells of various tissues (muscles, heart or liver). Life-threatening problems with the heart and/or respiratory tract occur. Early enzyme replacement therapy can limit glycogen deposition in various organs, but its effectiveness remains variable, especially in children. The team tried to intervene even earlier: they treated the child in utero.

Immune condition that interferes with treatment

Enzyme replacement therapy is an approach used in the case of several genetic diseases, which consists in the introduction of an artificially created enzyme to replace the missing enzyme. The earlier this treatment is started, the better the results. Babies with Pompe disease are often treated shortly after birth with replacement enzymes to slow the damaging effects of the disease.

However, the most severely affected infants have an immune condition in which their bodies block the injected enzymes, which eventually stops the therapy from working.

Both Zahid Bashir and Sobia Qureshi carry the recessive gene for Pompe disease, meaning their child has a one in four chance of inheriting the disease. The couple have a son, Hamza, 13, and a daughter, Maha, 5, who were unharmed; on the other hand, they have already lost two daughters, Zara at the age of 2 and a half years and Sarah at the age of 8 months due to illness. At the end of 2020, Zahid and Sobia learn that they are expecting another child, but prenatal tests show that she has Pompe disease.

To put the odds in her favor, little Ayla Bashir took advantage of an unprecedented intervention: enzyme replacement therapy was administered while she was still in the womb. She thus became the first child to be treated in utero for Pompe disease. With a needle inserted into her mother’s abdomen and through a vein in her umbilical cord, Isla received six infusions of enzymes every two weeks starting at 24 weeks pregnant.

Promising but still uncertain outcome

Isla was born in Ottawa, Ontario. She underwent standard postpartum therapy. Researchers report that she has normal heart function and age-appropriate motor function after birth, completed milestones, normal biomarker levels, was well fed and was growing at 13 months of age. “It’s a silver lining that they can be treated in utero rather than waiting until the damage is well established,” said Dr. Karen Fung-Ki-Fung, a maternal and fetal health specialist at Ottawa and Co. Hospital. – author of an article describing the intervention.

Doctors treated fetuses before they were born for thirty years, including surgeries to correct birth defects such as spina bifida. Blood transfusions were also carried out to the fetus through the umbilical cord. But never before has fetal drug treatment been applied in this way. “The innovation here was not the drug or access to the fetal circulation. The innovation was to treat earlier and treat while she was still in the womb,” said Dr. Pranesh Chakraborty, a metabolic geneticist at Eastern Ontario Children’s Hospital who has been caring for Ayla’s family for many years.

Although it is too early to finalize this protocol and confirm that it leads to better results, this case expands the field of potential fetal treatments. For Dr. Brendan Lanfer, a medical geneticist not involved in the study, this ultra-early treatment could be a real game-changer: “This is a progressive disease that develops over time, so every day that a fetus or baby has it, it accumulates more material that affects muscle cells,” he said.

Isla’s outlook is promising but remains uncertain. The team hopes this early treatment will lessen the severity of the immune response that blocks the action of the enzymes. The girl is currently on immunosuppressive therapy and receives weekly enzyme infusions that last five to six hours. If no new treatment comes along, she can expect to be on that treatment for the rest of her life.

J. Cohen et al., New England Journal of Medicine.

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