Scientists have used gene therapy to sharply reduce joint swelling from arthritis in rabbits. The finding, reported in this week's Proceedings of the National Academy of Sciences, could someday lead to a novel treatment for inflamed joints in people.
In arthritic joints, immune cells cause neighboring tissue to release proteins that trigger swelling, tissue degradation, and pain. Attempts to block these molecular signals--called IL-1 and TNF-a--have unpleasant side effects, such as broad immune suppression. Paul Robbins, a molecular geneticist at the University of Pittsburgh Medical School, thought that if he could get local cells to produce free-floating receptors for IL-1 or TNF-a, they could mop up excess molecules in the joint.
Robbins and his colleagues altered adenoviruses to carry IL-1 and TNF-a soluble receptor genes. Next they injected into the knees of arthritic rabbits adenovirus expressing either IL-1 receptor, TNF-a receptor, both receptors, or a control protein. Rabbits that received just the TNF-a showed little improvement relative to the control. However, those that received either IL-1 alone or with TNF-a had up to 85% fewer white blood cells and 65% less cartilage erosion in the injected knee.
To Robbins' surprise, the uninjected knees of the IL-1-treated rabbits also improved. "At first I thought the postdoc had screwed up," he says. To double-check, the group injected adenovirus carrying the luciferase gene, which makes a protein that glows and can easily be spotted. They found luciferase protein in white blood cells of the uninjected knee. Robbins thinks the white blood cells might ferry therapeutic genes to other inflamed joints. Gene therapy could be a good option for arthritis patients because all joints could be treated with a single injection, says Robbins.
"I am very excited about this work," says Susana Serrate-Sztein, director of the rheumatology branch of the National Institute of Arthritis and Musculoskeletal and Skin Diseases in Bethesda, Maryland. Delivering more than one gene is a useful feature, she says, since arthritis can be caused by several immune proteins. Robbins points out, however, that adenovirus may not be a good gene carrier in people because the virus itself causes inflammation.