Gene therapy for arthritis works in rats.

Cytokines are proteins that mediate communication between cells. In an immune response, they rally the body's white blood cells to an injury or infection site. One cytokine, called transforming growth factor (TGF) beta, often acts as the level-headed protein of the group, encouraging the troops not to overpopulate a region and cause inflammation.

Scientists studying arthritis now find that injecting laboratory rats with genes that encode TGF-beta protein can reduce inflammation in the rodent's joints. In the rats' muscle cells, these strings of DNA spur the rats' own cells to manufacture the protein, slowing the animals' arthritis, the researchers report in the June 15 Journal of Clinical Investigation.

While such gene therapy for arthritis is still many years away from widespread use, scientists have pursued it in human and animal studies in the hope of replacing anti-inflammatory drugs that cause side effects. Most gene therapy researchers use one of two kinds of viruses, adenoviruses and retroviruses, as delivery vehicles carrying desirable DNA. Neither, however, is perfect. Adenoviruses, in fact, can themselves ignite inflammation, the very condition being treated in arthritis.

In this study, researchers left the viruses out, using DNA from Escherichia coli bacteria to transport human TGF-beta DNA. "We thought we would [use] the naked DNA, without the viral vector," says study coauthor Sharon M. Wahl, an immunologist at the National Institute of Dental Research in Bethesda, Md.

Wahl and her colleagues used fragments of streptococcal bacteria to give dozens of rats arthritis. Some rats were left untreated as a control group. Others received a single injection of the TGF-beta-encoding genes in a muscle away from the swollen joint 5 to 13 days after arthritis had set in. Researchers measured swelling in the rats' ankle and wrist joints daily for at least 4 weeks and in some animals for up to 3 months. The treatments largely eliminated any arthritic inflammation, and even suppressed erosion of bone and cartilage--indicating that cells were producing TGF-beta.

"I must admit, I didn't think it would work so well," Wahl says. Examination of the rats' muscle tissue showed the DNA had been incorporated into the cells, she says.

"Other studies have used naked DNA," says William P. Arend, a rheumatologist at the University of Colorado in Denver. "What's most interesting here [is that] the effect of a single injection was sustained for a long period of time."

Injections of the TGF-beta-encoding genes directly into the inflamed joints exacerbated swelling, indicating TGF-beta may recruit more immune cells to the site if placed there directly, Wahl says. Injecting the genes at a remote muscle site allowed TGF-beta to follow a normal circulatory course to arrive at the location of the arthritis and stabilize the immune process, she suggests.