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New compound holds promise for treating lupus and related diseases

The discovery of a chemical compound by a charter member of the Life Sciences faculty, and several colleagues at U-M and the University of California, Berkeley, could lead to safer and more effective drugs for treating lupus and other autoimmune disorders.

A chemical cousin of anti-anxiety medications, such as Valium and Xanax, significantly reduces kidney inflammation in mice inbred to develop a disease resembling human systemic lupus erythematosus (SLE), says U-M organic chemist Gary D. Glick, a lead author of the study.

The research, described in the Oct. 16 issue of the Journal of Clinical Investigation, also reveals the novel mechanism by which the compound works.

"The best available therapies for lupus haven't changed for many, many years," Glick says. "It's a disease where the mechanisms that normally prevent the immune system from attacking components of one's own body are defective. Because we do not yet understand what triggers lupus, it has been very difficult to develop lupus-specific therapies."

In fact, the mainstays of treating lupus-related kidney inflammationa major cause of illness and death in lupus patientsare drugs developed many years ago to kill cancer cells. When given to lupus patients, often in combination with immune-suppressing steroids, these cytotoxic agents kill immune cells. But because they lack specificity, they also kill healthy cells, resulting in serious side effects. What's more, they simply are not effective in some patients.

"Our compound, on the other hand, goes in and kills the bad players but leaves the good players alone," says Glick, the Werner E. Bachmann Collegiate Professor of Chemistry and a professor of biological chemistry in the U-M Medical School.

The compound, a 1,4-benzodiazepine (designated as Bz-423), sets off a chain of events that results in apoptosis, a natural cell-suicide process by which the body rids itself of cells it no longer needs. In autoimmune disorders such as lupus, something interferes with apoptosis, and immune system cells survive and run amok instead of dying on cue. The abnormally surviving immune system cells produce antibodies, which attack the body's healthy cells and tissues. The result is harmful and sometimes fatal inflammation in various tissues and organs, particularly the kidneys.

"The results suggest that Bz-423, when administered appropriately, may have a significant therapeutic potential for lupus," Glick says.

According to the Centers for Disease Control and Prevention, lupus affects 1.4 million Americans, and more than 22,000 have died as a result of the disease during the past 20 years. Women of childbearing age are at greatest risk, and African Americans are more likely than Caucasians to develop the disease, says Dr. Anthony Opipari, assistant professor of obstetrics and gynecology and a lead author of the study.

There is evidence that Bz-423 may be useful in treating some types of cancer, as well as other autoimmune diseases, and the researchers are actively pursuing these possibilities, Opipari says.

In addition to Glick and Opipari, U-M authors of the paper include M.D.-Ph.D. students Neal B. Blatt, Jeffrey J. Bednarski and Kathryn M. Johnson; Anthony Boitano, doctoral student in chemistry; Roscoe L. Warner, research investigator in pathology; Dr. Raymond L. Yung, assistant professor of internal medicine; Dr. Bruce C. Richardson, professor of internal medicine; and Dr. Kent J. Johnson, professor of pathology. The research was funded by the National Institutes of Health and the U-M Multipurpose Arthritis Center.

 

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