Article summary
With six treatments of enzyme replacement therapy, children with Pompe disease were born without myocardial thickening, achieved normal developmental milestones, and were able to walk independently by one year.
Enzyme replacement therapy (ERT) as soon as possible after birth is the standard treatment for Pompe disease, a glycogen storage disorder. This is because there is the greatest hope of stopping the tissue damage caused by glycogen accumulation that begins in the uterus.
Well, a new paper was published on November 9th. New England Journal of Medicine Suggests to provide ERT intrauterine It may be even more beneficial. In a case report, with six additional treatments, a child was born without myocardial thickening, achieved normal developmental milestones, and was able to walk independently by 12 months.
Pompe disease is an autosomal recessive disorder caused by a deficiency of acid alpha-glucosidase (GAA), which is required for lysosomal glycogenolysis. Without it, glycogen accumulates in lysosomes, leading to lysosomal rupture, impaired autophagy, and other pathophysiological consequences. Myopathy, particularly hypertrophic cardiomyopathy, and respiratory and movement disorders, develop at birth or shortly thereafter. Untreated, it progresses rapidly and is often fatal within the first two years of life.
First approved in the US in 2006, ERT can have a significant impact on disease course if initiated early. Biweekly infusions of recombinant GAA arrest or reverse cardiomyopathy and significantly improve survival, but with less benefit to skeletal muscle.
“Hopefully, these babies will get a very head start. If they start with less damage at birth, the enzyme therapy can keep up with the glycogen build-up and not have to catch up.” No.” – DR. Priya Sunil Kishnani
“Damage to organs, including the heart, begins in the womb,” said Tippi McKenzie, MD, senior author of the report, professor of surgery and co-director of the University of California’s Center for Maternal-Fetal Precision Medicine. I’m here. San Francisco, School of Medicine.
Dr. Mackenzie is also director of the Eli and Edith Broad Center for Regenerative Medicine and Stem Cell Research at the University of California, San Francisco, and her colleagues have shown that prenatal administration of enzymes can prevent the accumulation of tissue damage. I theorized that it could.
They designed a clinical trial to offer ERT intrauterine in nine different lysosomal storage diseases, including Pompe, Gaucher, and Wolman disease plus five subtypes of mucopolysaccharidosis. These conditions are rare, even more so in patients with prenatal diagnosis. The trial was designed to enroll 10 subjects with affected fetuses and is still open for enrollment.
A subject in the present report was pregnant with a fetus diagnosed with Pompe disease confirmed by chorionic villus sampling. My parents are of Pakistani descent and lived in Canada. The family had two children who died of infantile-onset Pompe disease. Dr. Mackenzie said her mother met the entry criteria and was included in the report, but because she was not in the United States, she was unable to enroll in the trial.
Treatment with ERT was initiated at gestational week 24, gestational day 5 and 20 mg/kg recombinant GAA was injected into the umbilical vein as a standard postnatal dose. This regimen was repeated every 2 weeks up to 34 weeks 5 days for a total of 6 prenatal injections. The needle was placed using ultrasound guidance.
This procedure was very similar to procedures used elsewhere in fetal medicine, including fetal anemia due to Rh factor incompatibility, so many people know how to perform this procedure.
The most severely affected infants with Pompe disease are those who have no endogenous enzyme activity (as in the current report) and therefore mount an immune attack when the enzyme is introduced. likely to
Therefore, part of the standard treatment protocol is to initiate immunosuppression at the same time as ERT and continue for 5 weeks until resistance to the new protein develops. In the current case, immunosuppression was postponed until delivery. It is not yet clear whether prenatal introduction of the enzyme is sufficient to develop immune tolerance.
Children were delivered 37 weeks, 3 days and 3 weeks after the last injection. Creatine kinase, which is usually elevated in infants with Pompe disease, was normal at birth and remained normal throughout 13 months of follow-up. It was normal. Children developed gross and fine motor skills in an age-appropriate manner, and by 10 months were between the 50th and 75th percentiles on the Alberta Infant Motor Scale. She started walking at 11.5 months.
Both prenatal and postnatal echocardiograms were normal, contrasting with the severe left ventricular hypertrophy seen at 34 weeks of gestation in the prenatally scanned brother. Contrary to previous pathological reports of infantile-onset Pompe disease patients, there was no accumulation of glycogen in the placenta of the present patient.
intrauterine Treatment for Pompe disease “provides enzymes when needed to prevent thickening of the heart muscle,” says Dr. MacKenzie. “I think that’s why it made such a big difference.”
“Hopefully, we can give these babies a very head start,” said Priya Sunil, professor of pediatrics and director of the Department of Medical Genetics at Duke University School of Medicine, and co-lead author of the study. Kishnani, M.D. added: “If you start with less damage at birth, enzyme therapy doesn’t have to catch up and it can catch up with glycogen buildup.”
Dr. Mackenzie said the surgery was risky because “it puts a needle into the umbilical vein, which is the lifeline of the fetus.” Discussing that risk and weighing it against potential benefits is a very important part of the conversation. [to have] with my family,” she said.
She added that it’s also important to remember that while a child is doing well, she’s not healing. But it doesn’t fix the root cause.
“intrauterine Treatment has helped improve her prognosis, but she will need lifelong therapy,” said Dr. Mackenzie.
Expert commentary
“This is a very exciting development in the treatment of Pompe disease,” said Damara Ortiz, M.D., Ph.D., assistant professor of pediatrics and director of the Lysosomal Storage Disorders Program at the University of Pittsburgh School of Medicine. “Those of us who care for these children know that the sooner treatment is given, the better the outcome, especially in children with inactive enzymes.”
A 2021 study found that. genetic medicine The results showed that even a one-week delay in starting postnatal treatment affected milestone achievement at one year.
Number of target families intrauterine However, given that families need to be aware of their risks before being tested, treatment for Pompe disease is likely to remain very small.
Newborn screening for Pompe disease is now standard in 30 states, but no state requires prenatal testing. However, maternal testing may become more common. intrauterine Treatment has proven to be a major improvement in the disease.
If the mother tests positive, the father can also be tested. If he is also positive, fetal testing may be offered.
“Not all families terminate affected pregnancies,” Dr. Ortiz said. intrauterine If ongoing trials are successful and the treatment is approved by the U.S. Food and Drug Administration, the treatment could give families another option.
one of the potential benefits intrauterine Treatment may save associated medical costs later in life. ERT costs upwards of $100,000 annually, but significant reduction in cardiac and skeletal muscle problems can significantly reduce the need for other medical services. Early treatment “may reduce total lifetime costs,” Dr. Ortiz said.
“It remains to be seen whether these additional six treatments will affect long-term outcomes,” said director of the Powell Center for Gene Therapy and professor of pediatrics and molecular genetics and microbiology at the same university. One Barry Byrne, M.D., said: in Gainesville, Florida. “However, this study provides insight into what is possible in fetal medicine, and really opens the door to earlier treatments with other modalities, particularly gene therapy.” Gene delivery may eliminate or reduce the need for ERT.
one advantage of intrauterine According to Dr. Byrne, therapy is the potential for therapeutic enzymes or gene vectors to reach the brain before the blood-brain barrier closes. Cognitive involvement is minimal in Pompe disease, which is not the case in other lysosomal storage diseases.
“The good news is that several pharmaceutical and biotech companies are pursuing gene therapy for Pompe disease and other diseases,” Dr. Byrne said.
“For me, the outcome of this research is that it will increase our ability to safely access the fetus in this way, and provide other treatments that may have an even greater impact if obtained early.”
Disclosure
Dr. Mackenzie serves on Acrigen’s Scientific Advisory Board, and her institution has received research funding from BioMarin Pharmaceuticals and Novartis. Dr. Kishnani has received research/grant support, consulting fees and honoraria from Amicus Therapeutics, AskBio, JCR Pharmaceutical, Maze Therapeutics and Sanofi Genzyme. Dr. Kishnani is a member of Amicus Therapeutics’ Pompe & Gaucher Registry Advisory Board and she has her options in stock in AskBio (Asklepios Her Biopharmaceutical)..
Dr. Ortiz has received research grants and honoraria from Sanofi (formerly Sanofi-Genzyme) and Amicus. Sanofi manufactures alglucosidase alfa (Lumizyme) and avalglucosidase alfa-ngpt (Nexviazyme). Amicus is investigating alternative ERT + SRT therapies..
