Skip to main content
HHS Logo U.S. Department of Health & Human Services Divider arrow NIH logo National Institutes of Health Alt desc
Stories and Publications

NCATS’ Pre-Clinical Collaboration Enables Gene Therapy for Rare Muscle Disease to Advance to Clinical Trial

Translational Science Highlight

  • NCATS scientists collaborated with NIH-funded researchers at Duke University to advance a gene therapy for a rare neuromuscular disorder toward clinical testing. The work also has implications for other diseases because it shows how gene therapy can affect the immune system.

NCATS Therapeutics for Rare and Neglected Diseases (TRND) researchers and scientists at Duke University’s Clinical and Translational Science Institute (CTSI) have helped advance a gene therapy for Pompe disease into clinical testing for the first time. Patients with this rare, often deadly muscle disorder have a faulty gene that does not make enough of an enzyme, acid alpha-glucosidase (GAA), needed to break down glycogen — sugar stores — in the body. Glycogen buildup in muscle cells results in abnormal development; if left untreated, Pompe disease can lead to respiratory problems, heart failure and death. This therapy uses a modified virus to deliver a healthy gene to a patient’s liver, which then acts like a GAA factory, churning out the missing enzyme into the bloodstream and to muscle cells.

“We completed experiments demonstrating the advantages of gene therapy for Pompe disease in mouse models and had convincing evidence for its use in patients,” said principal investigator Dwight Koeberl, M.D., Ph.D., a medical geneticist and professor of pediatrics at Duke University. “A collaboration with NCATS, through its TRND program, helped overcome therapy development obstacles — including manufacturing a virus supply needed to deliver the healthy gene and navigating the complex regulatory development processes — to make clinical testing possible.”

An illustration of how gene therapy can work in a patient with Pompe disease, an inherited muscle disorder caused by a faulty gene.

This is an illustration of this gene therapy approach for Pompe disease, a deadly, inherited muscle disorder caused by a faulty gene. This image depicts a modified virus, called rAAV 8, being injected into an individual and carrying a healthy gene to the liver. Once in the liver, the gene produces a missing enzyme, called GAA, which goes to the muscles and helps them work. Based on mouse studies, the researchers also expect the gene therapy to train the body’s immune system to recognize GAA and not attack it.

Koeberl and Duke University School of Medicine scientists will begin a clinical trial in fall 2018 funded by the National Institute of Arthritis and Musculoskeletal and Skin Diseases, with support from NCATS, to determine the safety of the therapy in 20 Pompe disease patients. 

“NCATS’ collaborative pre-clinical research led to the demonstration of a promising gene delivery approach,” said Nora Yang, Ph.D., director of portfolio management and strategic operations in NCATS’ Division of Pre-Clinical Innovation, where the TRND program is administered. “The rare disease focus of this project made it a natural fit with the TRND program, and it adds to NCATS’ growing experience with different gene therapy platforms.”

The current standard treatment for Pompe disease is enzyme replacement therapy (ERT), in which the missing GAA enzyme is directly injected into the body. Although ERT can be effective for many patients, it is expensive, requires injection every two weeks, and may not work for all patients with Pompe disease, especially those whose immune systems recognize the injected GAA as a foreign substance and attack the enzyme. Even for those patients in whom ERT initially works, the body can develop an immune response and eventually build a resistance to the therapy.

Last year, Koeberl’s team showed in animal studies that gene therapy appeared to cause the animals’ immune systems to recognize GAA so they wouldn’t attack it, making ERT more effective. ERT worked better in mice with Pompe disease even when the gene therapy doses were too low to produce enough GAA to improve muscle function. The researchers also showed that a small, single dose of gene therapy could be as effective as – or more effective than – ERT. They found that when Pompe disease mice produced high enough levels of GAA, the animals no longer needed ERT after gene therapy.   

“We would like to see this promising new therapy added to the ‘medicine chest’ for physicians to help treat and manage all patients with Pompe disease,” Yang said. “If the concept of using gene therapy to build immune tolerance works, there is the potential that we can apply the same principle to other diseases that involve problems with immune system intolerance for ERT to help many more patients who suffer from debilitating diseases.” 

The research was supported by NCATS through its TRND program, NIAMS grants R01-AR065873, U01-AR071693 and U34-AR064515, and Genethon.

Through its TRND program, NCATS scientists provide pre-clinical expertise and resources to move a potential therapy toward an Investigational New Drug (IND) application, which is required by the Food and Drug Administration prior to clinical testing. In limited cases, NCATS also provides TRND support for proof-of-concept human clinical studies.

Posted January 2018