Deadly disease treated in utero for the first time

An international medical team has managed to treat a rare and lethal genetic disorder in a baby before it is born – a first-of-its-kind in utero therapy.

In early 2021, Ayla Bashir was diagnosed in utero with the deadly disease known as infantile-onset Pompe disease, which had already killed two older siblings.

To try to avoid the complications of Pompe, such as heart damage and weakened muscles, which begin in utero, doctors used an experimental enzyme replacement therapy, delivering a crucial enzyme to Ayla directly through the umbilical vein.

She is now over a year old – and healthy.

An international medical team has managed to treat a rare and lethal genetic disorder in a baby before it is born – a first-of-its-kind in utero therapy.

The team, spread across UC-San Francisco, Duke University and Ottawa’s Children’s Hospital of Eastern Ontario (CHEO), needed to beat the clock and COVID to deliver enzyme replacement therapy in time for Ayla to be born healthy.

In addition to being the first successful example of the therapy, the work, published in the New England Journal of Medicine, can be seen as a proof of concept, “expanding the repertoire of fetal therapy,” said UCSF pediatric and fetal surgeon Tippi MacKenzie, who was involved in Ayla’s care, told STAT.

What is Pompe disease? Pompe disease is a rare, inherited and often lethal condition, belonging to a group of conditions known as lysosomal storage diseases, in which specific enzymes important for breaking down complex molecules are lacking.

In people with Pompe, genetic mutations prevent the body from producing an important enzyme called GAA. Without GAA, the body cannot break down a form of sugar that it stores as energy. When sugar builds up, heart and skeletal muscle cells suffer the most damage, leading to heart and muscle failure.

Enzyme replacement therapy is used to reduce this buildup, maintain heart muscle, and improve skeletal muscle.

Administration of enzyme replacement therapy in utero allowed the patient to be born without the life-threatening complications of Pompe disease.

The prognosis for patients with infantile-onset Pompe disease – those for whom it begins in utero – is dismal. Without enzyme replacement therapy, their hearts thicken and enlarge until they die of cardiorespiratory failure or a respiratory infection – most within a year.

The Bashirs know this all too well – the family had already lost two children to the disease.

“She is a miracle,” said Ayla’s father, Zahid Bashir.

Fetal enzyme replacement therapy: 🇧🇷CHEO doctor Pranesh Chakraborty has been seeing the Bashir family since Pompe’s first diagnosis. When genetic screening results revealed that Ayla also had Pompe, Chakraborty had to design enzyme replacement therapy.

He contacted Priya Kishnani, head of medical genetics at Duke, for help, STAT reported. Kishnani’s colleague, Jennifer Cohen, was working with MacKenzie at UCSF, designing a clinical trial for in utero enzyme replacement therapy.

The teams realized that Ayla could be a test candidate.

In early 2021, COVID-19 restrictions blocked travel from San Francisco to Ottawa, where Ayla’s family lives, so teams shared all the necessary information digitally and began treatment.

Doctors at CHEO administered the enzyme six times, starting at 24 weeks of pregnancy, Science reported. When Ayla was born, she had no signs of the heart problems associated with childhood-onset Pompe and developed normally.

The work can be seen as a proof of concept for other in utero therapies.

Ayla is still receiving enzyme replacement therapy and will need to continue it indefinitely unless possible permanent therapies, such as stem cell transplants and gene therapies currently in clinical trials, become available, Kishnani and Cohen told Science.

“The hope is that if we can prevent neurological damage in utero, we can stop the progression and hopefully serve as a bridge.”

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Deadly disease treated in utero for the first time

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