Kids with Pompe disease fail because of a missing enzyme, GAA, that leads to dangerous sugar build-up, which affects muscles and movement.
An enzyme replacement treatment pioneered at Duke University has saved many lives, but some children with Pompe disease produce an immune reaction that blocks the benefits of the life-saving enzyme treatment.
To date, there has been no success in eliminating or suppressing this immune response.
Now research led by Duke University Medical Center, with collaborators at other centers, has resulted in successful enzyme replacement therapy for children who were predicted to have or who had the immune reaction blocking the effects of the enzyme therapy. In the past, children with this immune response died despite treatment.
In an article appearing in Genetics in Medicine, the researchers showed that a very low-dose combination of medicines typically used to treat cancer was successful in eliminating or preventing the immune response.
The drugs were rituximab, methotrexate and gammaglobulins -- a mix of chemotherapeutic drugs and drugs to support the immune system. These drugs were the right mix for children who had Pompe, and who most likely weren't going to benefit from the enzyme treatment because of their anti-GAA immune response.
"The goal is to get the new combination therapy to the child who is at risk of rejecting the enzyme, before or at the time the enzyme (recombinant human GAA (rhGAA), known as Myozyme) is infused," said senior author Priya Kishnani, MD, professor of pediatrics and medical genetics at Duke.
"If you can get this combination to people early, before they are infused with the enzyme, they will likely have a very good response to the enzyme treatment. Once the body has been exposed to the enzyme treatment, the babies at risk are likely to mount an immune response that blocks the effectiveness of the infused enzyme."
The group at Duke earlier showed the role of the immune response in children with Pompe disease. Once this response occurred, children who were previously doing well failed to benefit from treatment and died.
The researchers in the current study, spread out in centers at Children's Hospitals & Clinics of Minnesota, Medical College of Wisconsin/Children's Hospital of Wisconsin, Sorka Medical Center in Israel, and the Evelina Children's Hospital in London, worked together to treat the at-risk babies with the chemotherapy medicines at the time enzyme treatment started or shortly thereafter.
The team at Duke used genetic sequencing to identify the children at risk of enzyme-treatment failure. The experience of the Duke group allowed for identification of these cases early.
Senior author Kishnani said the stakes of failure are very high. "Until now, children with Pompe who make antibodies to the enzyme treatment die or are placed on invasive ventilation by age 27 months," she said. "It is very difficult for families, because some children who initially showed a benefit and were able to walk then started failing once the immune response occurred. It is heartbreaking to watch, not only for family members, but also for the team that cares for the children."
The study examined four children -- two who had Pompe and had never been treated and two who were treated, but were failing.
"We have made a difference in the lives of four patients at medical centers around the world," Kishnani said. "All of them have achieved new motor abilities, in distinct contrast with the relentless downhill course of patients who were unable to tolerate the enzyme therapy and would otherwise have died." Some of these children have now been doing well for a number of years, Kishnani said.
Other authors include Deeksha Bali and Sarah P. Young of Division of Medical Genetics, Duke Department of Pediatrics; Laura E. Case of the Duke Division of Physical Therapy, Department of Community and Family Medicine; Yoav H. Messinger of Pediatric Hematology/Oncology, and Nancy J. Mendelsohn and Rebecca Olson of Medical Genetics, at Children's Hospitals & Clinics of Minnesota; William Rhead, Amy White, Cara Wells and David Dimmock of the Division of Genetics, Departments of Pediatrics, Medical College of Wisconsin and Children's Hospital of Wisconsin; Eli Hershkovitz of Pediatric Endocrinology & Metabolism Unit, Soroka Medical Center, Beer Sheva, Israel,; Michael Champion of the Department of Inherited Metabolic Disease, Evelina Children's Hospital, London, United Kingdom; Simon A. Jones of Genetic Medicine, Manchester Academic Health Science Centre, Central Manchester University, Manchester, UK; and Amy S. Rosenberg of the Division of Therapeutic Proteins, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Bethesda, Maryland.
Dr. Kishnani received research funding and honoraria from Genzyme, and is a member of Pompe and Gaucher Disease Registry Advisory Boards for Genzyme. Dr. Case also received research support from Genzyme, and PTC Therapeutics, Leal Foundation, families of SMA, and grant support from the National Skeletal Muscle Research Center, and is also a consultant for the Genzyme registry advisory boards. Several other authors received research funding or honoraria from or consult for Genzyme.
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