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Gene therapy succeeds in mouse and rat models of diabetes
By Bijal P. Trivedi

Researchers have used gene therapy to reverse the symptoms of Type 1 diabetes mellitus, or juvenile diabetes, in mice and rats for up to eight months. Within two weeks of receiving a new insulin-like gene, diabetic rodents controlled their glucose levels. While the experimental therapy is still about 3 years from human clinical trials, it offers hope for treatments others than daily regimen of insulin injections.

The challenge when treating juvenile diabetes is to engineer a system that responds to minute-by-minute changes in glucose levels. Gene therapy researchers from Canada and Korea designed an insulin-like gene (SIA) and coupled it to a glucose-sensitive molecular switch. "It is like a thermostat, but for glucose," says Ji-Won Yoon, of the University of Calgary, Alberta, Canada. "When glucose levels are too high the SIA gene is turned on; when glucose levels are low the gene is off."

When healthy and diabetic rodents were given glucose shots, their bodies responded by releasing insulin or SIA. In healthy animals, insulin causes the glucose levels to return to normal in 90 minutes, while in diabetic animals carrying the SIA gene the glucose levels took 120 minutes to reach the same point. These results are published in this week's issue of Nature. "The delayed response in animals carrying SIA doesn't seem to be a problem because the final glucose levels are the same in healthy and diabetic animals, and there do not seem to be any side effects," says Yoon.

Key to the success of this experiment was the design of SIA, according to Jerrold Olefsky, of the University of California, San Diego. Olefsky wrote a News and Views piece that accompanies Yoon's report.

The SIA gene engineered by Yoon and his colleagues produces a slightly altered version of insulin that is produced in the liver. Natural insulin is produced in the pancreas. In juvenile diabetes the insulin-producing cells have been mistakenly destroyed by the immune system, which necessitates that any substitute is made elsewhere in the body.

There are still many hurdles to overcome before Yoon and his collaborators at Yonsei University in Seoul, can progress to human trials. The scientists used a virus to deliver SIA to the liver cells of diabetic rats and mice. The amount of virus required to treat larger animals such as dogs and monkeys must be determined before moving on to humans. Studies of how the expression of SIA changes over time are also needed.

Olefsky also points out that rats have a higher rate of metabolism and thus the SIA may work well in rodents, but the results may not carry over to humans. Another concern is that abnormally low sugar levels can occur if the gene is not tightly controlled. When the blood sugar level drops too low brain functions can be impaired. Lower glucose levels were seen in animals carrying the SIA gene, but whether this same effect will be seen in larger animals is difficult to predict.

People with Type 1 diabetes are unable to process and store glucose and rely on a daily regimen of insulin injections. Without insulin the high blood glucose levels would eventually lead to death.

Most therapeutic responses have focused on direct delivery of insulin through injections. But insulin shots can be painful and expensive. Transplanting insulin-producing pancreatic cells from healthy donors is another form of therapy, but transplantation ties the patient to a life of immunosuppressive drugs to prevent rejection.

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Lee, H. C. et al. Remission in models of type 1 diabetes by gene therapy using a single-chain insulin analogue. Nature 408, 483-488 (November 23, 2000).

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