UF Explores Gene Therapy And Marine Sponges In Fight Against Diabetes

November 20, 2001

GAINESVILLE, Fla. — In separate papers published today, University of Florida scientists and their colleagues announced two distinct approaches for thwarting the onset of type 1 diabetes in mice susceptible to the disease.

One team injected copies of a gene that manufactures a key immune system protein. The other group – in partnership with Dana-Farber Cancer Institute researchers – used fat molecules, taken from marine sponges, that appear to activate certain immune system cells that help reduce inflammation in the pancreas.

The underlying goal of both projects: Reset the immune system to prevent it from attacking the body’s own insulin-producing cells, the self-destructive event that causes diabetes. Both techniques are described in the Nov. 20 Proceedings of the National Academy of Sciences.

“These two approaches work in very different ways, but they both represent a considerable research interest in trying to change the immune system environment so that the attack is interrupted,” said Mark A. Atkinson, an author of the gene-therapy paper and director of the Juvenile Diabetes Research Foundation Gene Therapy Center for the Prevention of Diabetes and Its Complications at UF and the University of Miami.

“We’re optimistic, but it’s important to remember that these findings are in animals and considerable research remains to be done,” said Atkinson, the Sebastian Family/American Diabetes Association professor for diabetes research at UF.

The use of marine sponge lipids currently is being tested in human clinical trials for cancer. If the tests demonstrate that the treatment is safe, clinical trials for diabetes may soon follow.

An estimated 1 million people in the United States have type 1 diabetes, a chronic disease treated with daily injections of insulin to help regulate how the body uses and stores sugar and other nutrients. Many people suffer major complications, including damage to blood vessels, which can lead to heart disease, stroke, blindness, kidney failure and the need for lower limbs to be amputated.

In recent years, scientists have been trying to understand the quiet but destructive events that occur in the body in the months and even years preceding the onset of disease symptoms. This knowledge, they hope, will help them identify opportunities for derailing the disease process.

Previous studies involving protein strategies have shown that disease can be prevented by injecting mice prone to developing diabetes with immune-system proteins IL-4 and IL-10. However, UF researchers say it would not be practical in humans to give repeated doses of the proteins.

That’s why they turned to gene therapy as a one-shot means to deliver the treatment. The idea is to increase the animals’ supply of genes that can manufacture the proteins.

“With gene therapy, we can provide for a sustained low-level release of these proteins,” said Dr. Terence R. Flotte, director of UF’s Genetics Institute and Powell Gene Therapy Center, and a co-author on the paper focusing on the gene-therapy approach.

The experiments showed, however, that only the mice that received IL-10, either by itself or in combination with IL-4, were protected from diabetes.

Atkinson said that studies will continue in mice to determine how small a dose of gene therapy can be used to block the onset of disease, and how late in the disease development process they can administer the therapy effectively.

They also are exploring in mice whether gene therapy could help those that already have full-blown diabetes. One scenario: Improve the success rate of pancreatic tissue transplants by deploying gene therapy to prevent immune system attacks on implants.

In the other diabetes paper published today, scientists from UF and the Dana-Farber Cancer Institute described how fat molecules, or lipids from marine sponges, could increase the supply and activity of NKT cells of the immune system. In mice and humans, those with diabetes have fewer NKT cells than those without the disease, apparently compromising their ability to disrupt the attack by the immune system against insulin-producing cells.

Dr. Michael Clare-Salzler, an associate professor of pathology, immunology and laboratory medicine at UF’s College of Medicine, and Dr. Brian Wilson, an assistant professor of medicine at Harvard Medical School and a Dana-Farber researcher, were senior co-authors on the paper. Scientists from the Mayo Clinic of Rochester, Minn., also contributed to the research.

“What we found was that when we treated the animals with the sponge lipid, alpha-galactosylceramide, pancreas inflammation and diabetes were significantly reduced,” Clare-Salzler said. “What we and the Wilson laboratory demonstrated is that when NKT cells are activated by lipid treatment, they appear to interact with other key immune cells called dendritic cells. As a result of this interaction, the function of dendritic cells changes from one that promotes inflammation to one that potently regulates the destructive immune process that causes diabetes.”

Clare-Salzler said the lessons he and Wilson have learned about the NKT cells may prove helpful in understanding and treating other autoimmune diseases in which inflammation plays a role, including multiple sclerosis and rheumatoid arthritis.

Both diabetes research efforts were supported by grants from the Juvenile Diabetes Research Foundation and the National Institutes of Health. The marine sponge lipids were supplied by Kirin Brewery Pharmaceutical Co., which is exploring other therapeutic uses of the compound.