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Duke to begin clinical trials for Pompe disease gene therapy this fall

Wednesday, March 28, 2018
By Samiha Khanna
Dwight Koeberl

DURHAM, N.C. -- After decades pioneering treatments for 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 people with the rare, muscle-crippling disorder.

The experimental therapy uses a modified virus to deliver a gene to the liver, where it produces GAA, an enzyme missing in people with Pompe disease. The method was tested in mice, as described in a study published in 2017 in the journal Molecular Therapy - Methods & Clinical Development.

Researchers are currently screening adults with late-onset Pompe disease as they prepare for a phase 1 clinical trial to test the safety of the treatment in 20 people with the condition. The trial will be funded by the National Institute of Arthritis and Musculoskeletal and Skin Diseases, with support from the National Center for Advancing Translational Sciences. Both agencies are part of the National institutes of Health. The team also received support from the Duke Clinical & Translational Science Institute.

Pompe disease is an inherited condition that affects approximately 1 in 20,000 babies and can also appear in adulthood. Without the enzyme GAA, bodies can’t metabolize the sugar, glycogen. As a result, glycogen builds up in the muscles, leading to degradation of the tissue. If undiagnosed and untreated, it 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 Dwight Koeberl, MD, PhD, professor of pediatrics and a medical genetics specialist at Duke who developed the new therapy.

The enzyme replacement therapy (ERT), developed using foundational research from Duke, was heralded as a breakthrough for an orphan disease in 2006, and was dramatized in the major motion picture “Extraordinary Measures.”

“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.”

In the research published in 2017, the Duke-led research team found that a single small dose of gene therapy was as effective as 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 two to four times 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, which does not cause illness and has been used as a delivery system for hemophilia B and muscular dystrophy treatments, among others, Koeberl said.

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Research, Treatments for Pompe Disease Span Three Decades