Gene therapy corrects mouse lupus.

Researchers have used gene therapy to cure a lupuslike autoimmune disorder afflicting mice. They hope such research will lead to better therapy for humans suffering from systemic lupus erythematosus (SLE).

Lupus is a sometimes fatal disorder that can cause inflammation and injury to various parts of the body, including the joints, skin, kidneys, lungs, blood vessels, and central nervous system. People with lupus generate antibodies that launch an offensive against healthy tissue in their own bodies.

The mice that star in the new study develop a lupuslike condition also characterized by kidney disease, arthritis, and lung disease. John D. Mountz of the University of Alabama at Birmingham and his colleagues started that investigation with the knowledge that these mice suffered from a defect in a gene called Fas. They wondered whether this routant gene and its protein product caused the massive autoimmune disease afflicting these mice.

The scientists began their experiment by obtaining mouse embryos that had inherited two copies of the flawed gene. Next, they inserted a normal Fas gene into the embryos and returned them to the fallopian tubes of female mice.

Less than 3 weeks later, those murine rooms delivered their pups. The researchers then conducted tests to mare sure the inserted gene had turned on in T lymphocytes, a type of white blood cell. Sure enough, the genetically engineered mice appeared to manufacture healthy amounts of the normal Fas protein. The team describes its work in the March 15 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES.

For 5 months, the researchers observed the mouse pups, looking for signs of the autoimmune disorder. They found no indication of kidney or lung disease or arthritis. The genetically engineered mice also showed no overproduction of antibodies that home in on the body's own tissues.

Prior to this study, researchers didn't know if a mutant Fas gene by itself could cause this disorder. The new findings indicate that the flawed gene is responsible for the destructive symptoms in mice, comments Michael D. Lockshin of the National Institute of Arthritis and Musculoskeletal and Skin Diseases in Bethesda, Md.

Mountz explains that a normal Fas gene directs the production of a protein receptor that plays a key role in apoptosis, or programmed cell death. That cellular suicide is the body's way of destroying immune cells that have a dangerous propensity to attack healthy tissue. The new research suggests that immune cells with a defective Fas gene don't get the message to commit cellular hara-kiri. Rather than self-destruct, they continue to mount their blitz against the body,

Further studies with this mouse model may offer scientists a glimpse of the mechanism underlying apoptosis, says Philip Cohen, a researcher at the University of North Carolina at Chapel Hill. Scientists still don't have a detailed picture of how an immune cell commits suicide, he adds.

Does a defect in apoptosis lead to lupus in humans? Nobody knows for sure. However, Mountz's team has unpublished research indicating that some people with lupus have a defect in the same gene. More than one gene probably regulates apoptosis in humans, Mountz says. He speculates that a variety of gene defects may underlie this disorder.

Right now, physicians give lupus patients steroid drugs, which Mountz believes may control symptoms by triggering apoptosis. But steroids also produce serious side effects, he adds.

If researchers can pinpoint the exact defect in humans, they might develop a targeted way to initiate cellular suicide. "If you could correct [the defect] at any point, you could potentially terminate the disease," Lockshin says, noting that such a therapy remains far from reality as yet.