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The first test of in utero enzyme replacement therapy (ERT) proved safe and effective for a baby with infantile-onset Pompe disease, according to a case report.

An infant with cross-reactive immunologic material (CRIM)-negative infantile-onset Pompe disease -- the most severe end of the disease spectrum -- had no cardiac manifestations following treatment, compared to her two affected siblings who had cardiomyopathies, reported Tippi MacKenzie, MD, of the University of California San Francisco, and colleagues.

Additionally, there was no glycogen buildup in utero, which leads to clinical sequelae of infantile-onset Pompe disease at birth, the researchers wrote in the .

The baby also had normal creatine kinase levels and age-appropriate motor function at 13 months, suggesting the overall cardiac and musculoskeletal benefit of in utero ERT.

In addition, there were no adverse reactions to any of the six infusions in either the mother or the fetus, they reported.

These results are consistent with in utero ERT attenuating -- or even halting -- the disease process during the fetal period, MacKenzie and colleagues wrote. Additionally, with further research, the findings may support moving the window of treatment for these patients to the prenatal period to improve childhood outcomes, they said.

Co-author Priya Kishnani, MD, of Duke University in Durham, North Carolina, called the work "exciting," "cutting-edge," and a new frontier for patients with Pompe disease, noting that the baby is doing extremely well from a cardiac, motor, and developmental perspective.

"She is achieving age-appropriate motor milestones," Kishnani told 麻豆传媒. The baby began walking at around 11.5 months, and has done well on physical therapy and cardiac assessments conducted in Ottawa, she said.

"But in the space of rare diseases, everything begins with an N-of-1," Kishnani added. "We do need to watch this baby very carefully, so that we can continue to ensure that in the longer term, she is continuing to thrive."

In an , Ans van der Ploeg, MD, PhD, of the Erasmus MC University Medical Center in the Netherlands, said that if this report is a "harbinger," then in utero therapy for fetuses diagnosed with Pompe disease could have an effect on the future of treatment. She added that there is still much to clarify in further research, namely whether starting in utero therapy at 24 weeks' gestation sufficiently precedes the formation of the blood-brain barrier to prevent the neurologic manifestations of lysosomal disorders.

"The outcomes of this trial are keenly awaited," van der Ploeg wrote. "In the meantime, the developmental course of the current patient is encouraging."

Infantile-onset Pompe disease is a rare, rapidly progressing lysosomal storage disease caused by acid α-glucosidase (GAA) enzyme deficiency. Patients develop hypertrophic cardiomyopathy prenatally and hypertonia at birth, and left untreated, typically die by age 2. All of these reasons make infantile-onset Pompe disease compelling to treat in utero, MacKenzie and colleagues wrote.

In the case of most severe diseases that occur after birth, doctors treat them right away, MacKenzie told 麻豆传媒. But for genetic diseases that are diagnosed before birth, clinicians often wait until after birth to treat -- which sometimes amounts to months. "It just makes sense to treat someone at the time of diagnosis," MacKenzie said.

The investigators followed the protocols from the phase I clinical trial, , which is investigating safety and efficacy of enzyme therapies delivered in utero to treat eight lysosomal storage disorders.

Due to travel restrictions during the early COVID-19 pandemic, this patient couldn't travel from Canada to UCSF for enzyme infusions during pregnancy. Thus, trial investigators shared the protocol with clinicians at the University of Ottawa so she could be treated locally.

The 37-year-old woman had three previous pregnancies affected by CRIM-negative infantile-onset Pompe disease; two children died in early childhood, and one of the pregnancies was electively terminated. In the current pregnancy, the fetus was diagnosed with Pompe disease prenatally via chorionic villus sampling.

Investigators conducted six in utero ERT infusions at 2-week intervals, starting at 24 weeks and 5 days of gestation and continuing through 34 weeks and 5 days of gestation. During the infusions, they administered alglucosidase alfa through the umbilical vein at a dose of 20 mg per kilogram of estimated fetal weight.

After birth, the infant was treated with immune tolerance induction on her first day of life. Starting on day 4, she received ERT infusions every 2 weeks, receiving 20 mg per kilogram at each dose. Clinicians increased her dose at around 10 months, and again at 11 months.

Researchers analyzed creatine kinase levels, cardiac outcomes, placental pathology, IgG antidrug antibodies, and glucose tetrasaccharide levels. They compared the baby to her affected siblings, as well as to a small cohort of CRIM-negative, early-treated infants who were detected at newborn screening.

Labor was induced and the baby was delivered vaginally at 37 weeks and 4 days of gestation.

The infant had normal creatine kinase levels up to 13 months, compared to a cohort of four CRIM-negative infants who all had elevated creatine kinase levels.

Additionally, each of the patient's echocardiograms were normal. She had a normal left ventricular mass index on day 1 (39.47 g per square meter of body-surface area), unlike her two siblings and the cohort of CRIM-negative infants who were treated early.

The researchers noted that there may also be an immune benefit to treating fetuses in utero. After birth, this patient mounted a lower immune response to the enzyme therapy that was not clinically significant, in contrast to those who were only treated postnatally. However, the researchers urged caution with these results, stating that more research must be done before drawing conclusions on immune benefit.

MacKenzie and colleagues stated that direct umbilical-vein administration of these therapies can be safe, but as with any fetal intervention there is a risk of preterm delivery. Future participants in the trial at UCSF will confirm safety and efficacy of this approach, they added.

Co-author Pranesh Chakraborty, MD, of the University of Ottawa, told 麻豆传媒 that the work represents another step forward for patients with rare diseases and their families.

"I think there is a message of hope," Chakraborty added. "You sometimes hear societal conversation about, why do we go to this length for kids with rare diseases. They deserve the care."

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