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Duke Scientists Reverse a Rare Form of Muscular Dystrophy in Mice Using Gene Therapy

Posted on: August 03, 1999

News Release by Karyn Hede
Duke Medical Center News Office

August 2, 1999

Using a modified virus to deliver a therapeutic gene, scientists at Duke University Medical Center have shown that, in mice, they can reverse the damage caused by an inherited muscle-wasting disease with a single injected dose.

The study findings, which appear in the Aug. 3 issue of the Proceedings of the National Academy of Science (see abstract below), show for the first time that it appears possible to deliver a therapeutic gene product throughout all of the muscles of the body to reverse muscle wasting, a result that has implications for treating dozens of forms of muscular dystrophy.

The researchers note, however, that to date they have only demonstrated a short-term reversal of symptoms in laboratory mice, and further experiments are needed to determine if the approach could become practical for use in people.

The study is part of a large, collaborative effort at Duke to find an effective treatment for Pompe disease, a rare inherited disorder in which the body cannot process glycogen…. People born with Pompe disease have a defect in the enzyme…acid alpha-glucosidase (GAA), which normally processes glycogen and converts it to sugar.

Several forms of Pompe‚Äôs affects more than 5,000 people in the US…......Duke pediatric geneticist Y.T. Chen has been simultaneously pursuing….... replacing the missing GAA enzyme and replacing the faulty gene. The first method uses cells grown in the laboratory that secrete a special form of GAA that, when injected intravenously, is easily taken up by muscle cells and processed…... Chen and his colleagues have developed a way to make the enzyme in large quantities and licensed that technology to Synpac (N.C.) Inc., a drug development company….. (part of) Synpac Pharmaceuticals Ltd. of Cambois, England. The company is funding an on-going clinical trial to test the enzyme therapy in up to 3 infants at Duke…...

Chen collaborated with Dr. Andrea Amalfitano, a pediatric geneticist…and the two designed an experimental system to deliver the genetic information…..using a modified adenovirus….Amalfitano has developed a form of the virus that appears to be able to evade detection by the immune system…..The modified virus tends to normally infect liver cells since the liver filters all blood within the body….. (Human Gene Therapy, Feb. 1999).

“The liver normally makes and secretes a large number of enzymes and we used that to our advantage in designing our gene delivery system,” said Amalfitano .......When the researchers injected the virus containing the specially designed genetic information into a mouse that develops Pompe disease, the virus went to the liver, which then began making and secreting the special enzyme into the blood stream… The idea worked-the mice that received the modified GAA gene in their livers subsequently had reduced accumulation of glycogen in muscles throughout the body.

“The heart and diaphragm muscles appeared to be especially responsive to the treatment,” said Amalfitano. “This is significant because failure of the heart or respiratory muscles are the primary cause of death in many people with Pompe disease…..This is the first example of the simultaneous correction of multiple muscle groups after a single, simple, intravenous administration of a gene therapy vector,” Amalfitano said,. “a hurdle that has always made the potential of gene therapy to treat muscle disease very difficult to envision.”

A.J. McVie-Wylie, H. Hu, and T.L. Dawson of Duke and N. Raben, P. Plotz of the National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH also contributed to the work.

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