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

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


Duke Health News Duke Health News

DURHAM, N.C. - 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,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 University to find an effective treatment for Pompe disease, a rare inherited disorder in which the body can not process glycogen, a stored form of sugar the body needs for energy. People born with Pompe disease have a defect in an enzyme called acid alpha-glucosidase (GAA), which normally processes glycogen and converts it to sugar. The glycogen builds up in muscle tissues throughout the body, including the heart, causing the various muscles to degenerate.

Several forms of Pompe disease affect more than 5,000 people in the United States. If symptoms appear during infancy, the disease is usually fatal. It is usually less severe when symptoms first appear late in childhood, but life expectancy is greatly deceased. Although Pompe disease is a relatively rare disease, it is but one of a group of lysosomal storage diseases, which in total occur in about one in 5,000 births in the United States.

Duke pediatric geneticist Y. T. Chen has been simultaneously pursuing two avenues to treating the disease: 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 to a useful form. Chen and his colleagues have developed a way to make the enzyme in large quantities and licensed that technology to Synpac (North Carolina) Inc., a drug development company in Research Triangle Park, and its parent company, Synpac Pharmaceuticals Ltd. of Cambois, England. The company is funding an on-going clinical trial to test the enzyme therapy in up to three infants at Duke. The research is also supported by the Howard Hughes Medical Institute and a gift from the Garrette Foundation.

"We are hopeful that the enzyme therapy will be an efficacious first therapy for this devastating disease," Chen said. "However, we ultimately would like to correct the defect at the genetic level and this study shows us that this might be possible."

Chen collaborated with Dr. Andrea Amalfitano, a pediatric geneticist who studies ways to get genes inside cells, and the two designed an experimental system to deliver the genetic information encoding the GAA enzyme using a modified adenovirus, the common cold virus. Amalfitano has developed a form of the virus that appears to be able to evade detection by the immune system more so than other viruses used in gene therapy. The modified virus tends to normally infect liver cells since the liver filters all blood within the body, Amalfitano reported. He and his colleagues published the results of this work in the February 1999 issue of Human Gene Therapy.

"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. "We had to find a way to get the enzyme from the liver to all the muscles in the body, which is the major hurdle to overcome in designing gene treatments for muscle disorders."

Chen solved the problem by using the body's own system for enzyme delivery. He reasoned that the liver secretes a special form of the GAA enzyme that has a molecular signal attached. This special enzyme is recognized by muscle cell receptors, which then trigger the cell to take up the enzyme and direct it to where it is needed within the muscles.

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 of the animals. The researchers hoped that in this manner, the muscle cells could receive the enzyme without having to each be individually injected with the virus. 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."

If future studies prove successful, a gene therapy strategy such as the one devised by the researchers could allow the body to generate its own continuous supply of enzyme, by using the liver as an "enzyme factory" and eliminating the need for lifetime injections of the enzyme. "This is the first example of the simultaneous correction of multiple muscle groups after a single, simple, intra-venous administration of a gene therapy vector" Amalfitano said, "a hurdle that has always made the potential of gene therapy to treat muscle diseases very difficult to envision."

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