In a world first, a toddler is thriving after US and Canadian medical experts used a novel technique to treat her – before she was born – for a rare genetic disease that caused the deaths of two of her sisters. Ayla Bashir, a 16-month-old from Ottawa, Ontario, is the first child treated as a foetus for Pompe disease, an inherited and often fatal disorder in which the body fails to make some or all of a crucial protein.
Today, reports Time, she’s an active, happy girl who has met her developmental milestones, according to her father, Zahid Bashir and mother, Sobia Qureshi, who previously lost two daughters, Zara, two-and-a-half and Sara, eight months, to the disease. A third pregnancy was terminated because of the disorder.
In the New England Journal of Medicine, doctors describe an international collaboration during the COVID-19 pandemic that led to the treatment that may have saved Ayla’s life – and expanded the field of potential foetal therapies. The outlook for Ayla is promising but uncertain.
“It holds a glimmer of hope for being able to treat them in utero instead of waiting until damage is already well-established,” said Dr Karen Fung-Kee-Fung, a maternal-foetal medicine specialist at The Ottawa Hospital who gave the treatment and delivered Ayla.
Fung-Kee-Fung was following a new treatment plan developed by Dr Tippi MacKenzie, a paediatric surgeon and co-director of the Centre for Maternal-Foetal Precision Medicine at the University of California, San Francisco, who shared her research after the pandemic prevented Ayla’s mother from travelling for care.
Doctors have treated foetuses before birth for three decades, often with surgeries to repair defects such as spina bifida. And they’ve given blood transfusions to foetuses through the umbilical cord, but not medicines. In this case, the crucial enzymes were delivered through a needle inserted through the mother’s abdomen and guided into a vein in the umbilical cord. Ayla received six biweekly infusions that started at about 24 weeks of gestation.
“The innovation here wasn’t the drug and it wasn’t accessing the foetal circulation,” said Dr Pranesh Chakraborty, a metabolic geneticist at Children’s Hospital of Eastern Ontario, who has cared for Ayla’s family for years. “The innovation was treating earlier and treating while still in utero.”
The unusual partnership also involved experts at Duke University in Durham, which has led research on Pompe disease, and University of Washington in Seattle.
Babies with Pompe disease are often treated soon after birth with replacement enzymes to slow devastating effects of the condition, which affects fewer than one in 100 000 newborns. It is caused by mutations in a gene that makes an enzyme that breaks down glycogen, or stored sugar, in cells. When that enzyme is reduced or eliminated, glycogen builds up dangerously throughout the body.
In addition, the most severely affected babies, including Ayla, have an immune condition in which their bodies block the infused enzymes, eventually stopping the therapy from working. The hope is that Ayla’s early treatment will reduce the severity of that immune response.
Babies with Pompe disease have trouble feeding, muscle weakness, floppiness and, often, grossly enlarged hearts. Untreated, most die from heart or breathing problems in the first year of life.
In late 2020, Bashir and Qureshi had learned they were expecting Ayla and that prenatal tests showed she, too, had Pompe disease. In addition to the girls who died, the couple have a 13-year-old son and a five-year-old daughter who are not affected.
Both parents carry a recessive gene for Pompe disease, which means there’s a one in four chance a baby will inherit the condition.
Chakraborty had learned of MacKenzie’s early stage trial to test the enzyme therapy and thought early treatment might be a solution.
Ayla receives drugs to suppress her immune system and weekly enzyme infusions that take five to six hours. Unless a new treatment emerges, Ayla can expect to continue the infusions for life. She is developing normally – for now. Her parents say every milestone, such as when she started to crawl, is especially precious.
Study details
In Utero Enzyme-Replacement Therapy for Infantile-Onset Pompe’s Disease
Jennifer Cohen, Pranesh Chakraborty, Karen Fung-Kee-Fung, Marisa Schwab, Deeksha Bali, Sarah Young, Michael Gelb, Hamid Khaledi, Alicia DiBattista, Stacey Smallshaw, Felipe Moretti, Derek Wong, et al.
Published in the NEJM on 9 November 2022
Summary
Patients with early-onset lysosomal storage diseases are ideal candidates for prenatal therapy because organ damage starts in utero. We report the safety and efficacy results of in utero enzyme-replacement therapy (ERT) in a foetus with CRIM (cross-reactive immunologic material)–negative infantile-onset Pompe’s disease. The family history was positive for infantile-onset Pompe’s disease with cardiomyopathy in two previously affected deceased siblings. After receiving in utero ERT and standard postnatal therapy, the current patient had normal cardiac and age-appropriate motor function postnatally, was meeting developmental milestones, had normal biomarker levels, and was feeding and growing well at 13 months of age.
NEJM article – In Utero Enzyme-Replacement Therapy for Infantile-Onset Pompe’s Disease (Open access)
Time article – In a First, Doctors Treat a Fatal Genetic Disease Before Birth (Open access)
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