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Press Release
VA Researchers Develop Potential Gene Therapy for Diabetes
January 4, 2000
Washington -- Veterans Affairs researchers have performed gene therapy in animals that may offer new hope for the millions of people who suffer from diabetes, one of the country's leading causes of death and disability. When inserted into rat liver cells, a gene developed by the VA team drove the cells to produce insulin--the hormone needed to use glucose, a simple sugar that serves as the body's fuel. Just as important, the gene also shut down insulin production before blood sugar fell dangerously low.
Scientists previously had used genes to induce insulin production in rat cells, said study leader Peter Thulé, M.D., an endocrinologist at the Atlanta VA Medical Center and assistant professor of medicine at Emory University. "But the problem is that they produced too much insulin and the animals died from low blood sugar," he said. "The big hurdle has been to create an insulin gene that is regulated, that can create more insulin when needed and also turn itself off."
Thulé and colleague Jing-Ming Liu, M.S., presented their results today at the second annual meeting of the American Society of Gene Therapy. More than two months after receiving the new gene, they reported, treated rats with diabetes were still alive and healthy. "The potential of this kind of gene therapy is that diabetic patients would not have to give themselves insulin shots or make decisions about how much insulin to give," Thule said. "The gene would do that automatically."
Marked by high blood sugar and complications such as nerve and blood vessel problems, diabetes afflicts some 16 million Americans. In type II or adult-onset diabetes, the body makes too little insulin or uses the hormone inefficiently. Many people with this type of diabetes can control blood sugar with strategies such as diet and weight loss. In type I or juvenile-onset diabetes, however, insulin manufacturing cells of the pancreas are destroyed by a misguided immune system attack. Patients with type I diabetes need daily insulin injections to survive.
Attempts to design gene therapy for diabetes rest on the need to provide a new insulin gene to diabetic patients. While all human cells have a gene for insulin production, this gene is active only in the particular pancreas cells that manufacture the hormone. To enable tissues outside the pancreas to produce insulin, scientists must provide an additional insulin gene controlled by genetic switches that function in the new organ. These switches can then tell the organ's cells to make insulin when needed and shut down when further insulin would drop blood glucose too low.
Although researchers previously designed insulin genes that instruct liver cells to produce insulin, Thulé and Liu took the next step by adding on-off switches. Each gene in the body has a portion that turns it on and off--the so-called promoter. "We hijacked promoters from two entirely different genes, inserting one that turns on when exposed to glucose into the promoter region of a gene that turns off when exposed to insulin," Thule said. The result was a novel promoter turned on by glucose and off by insulin that the researchers attached to a human insulin gene provided by Genentech, Inc.
The VA team then used a harmless virus to ferry the new insulin gene into liver cells of rats that had received a drug to destroy insulin producing pancreas cells. Untreated rats exhibited all the signs of diabetes, but rats receiving the gene produced insulin when given glucose. Equally important, the new gene appeared to turn off insulin production before blood sugar fell dangerously low.
Although animals with the new gene have remained alive for more than two months, Thulé noted, the human insulin gene remains separate from the rat's own genetic material. With time cells carrying the foreign gene will be destroyed, and the gene will no longer work. The next step, Thulé said, is to identify a harmless virus that can carry the new insulin gene to a permanent spot in a cell's genetic material.
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