Gene therapy for Pompe disease effective in mice, poised for human trials

Jan 26, 2017

After decades investigating Pompe disease, Duke Health researchers have developed a gene therapy they hope could enhance or even replace the only FDA-approved treatment currently available to patients.

The gene therapy, demonstrated in mice, is described in a new study published online in the journal Molecular Therapy - Methods & Clinical Development. The therapy uses a modified virus to deliver a gene to the liver where it produces GAA, an enzyme missing in people with Pompe disease.

Study authors have received approval from the FDA to launch a Phase 1 clinical trial in humans and are currently working to secure funding.

People with Pompe disease lack the enzyme GAA, which means their bodies can't metabolize the sugar, glycogen. As a result, glycogen builds up in the muscles. In babies, this leads to improper muscle development and, if undiagnosed and untreated, can lead to respiratory problems, heart failure, and death.

"The outlook for Pompe disease is much improved since enzyme replacement has become available -- it can reverse involvement of the heart and prolong survival," said senior author Dwight Koeberl MD PhD, professor of pediatrics and a medical genetics specialist at Duke.

"But not everyone responds to this treatment," Koeberl said. "Many patients make some antibodies, and this can really interfere with treatment. Some infants still die from Pompe disease. Others have to add immune suppression to their treatment, which can lead to other complications. Gene therapy could help these patients."

The Duke-led research team found that a single small dose of gene therapy was as effective as enzyme replacement therapy (ERT) in clearing the buildup of glycogen from the muscles in mice. A larger dose offered superior results to ERT. A single treatment spurred the liver to continuously produce GAA without additional treatment, the study authors said. Enzyme therapy requires infusions once or twice a month to lower glycogen levels in the muscles.

Unlike ERT, the gene therapy doesn't trigger an immune response, a reaction that can limit successful treatment in about half of babies with Pompe. In fact, the gene therapy appeared to reverse immune responses in mice that had previously developed antibodies in response to enzyme replacement, Koeberl said.

The gene therapy uses an inactivated form of adeno-associated virus (AAV), which does not cause illness and has been used as a delivery system for hemophilia B and muscular dystrophy treatments, among others, Koeberl said.

The emerging gene therapy is just the latest development for a team of scientists at Duke that has been working for 3 decades to study the causes and potential treatments for glycogen-storage diseases and specifically Pompe.

The research was supported by the National Institute of Arthritis and Musculoskeletal and Skin Disorders, part of the National Institutes of Health (R01AR065873) and by Genethon.

Author disclosures: Koeberl developed the technology that is being used in the study. If the technology is commercially successful in the future, the developers and Duke University may benefit financially. He has received research and grant support from Sanofi Genzyme Corporation in the past, and the rhGAA (enzyme replacement agent) used in these studies was supplied by Sanofi Genzyme. 

Source: News Release
Duke University Medical Center
January 26, 2017