ANN ARBOR—A new drug candidate previously found to be effective in reducing harmful side effects of the autoimmune disease lupus also works to prevent arthritis-related complications without damaging normal immune system function. In a study published in the March edition of the journal Arthritis & Rheumatism, scientists from the University of Michigan and University of California, Berkeley report that a compound called benzodiazepine-423, a chemical cousin of the drugs Valium® and Xanax®, reduced the effects of both systemic lupus erythematosus and arthritis in mice. A healthy immune system recognizes friend from foe to protect the body against invading bacteria and viruses. But in lupus and arthritis, the cells of the immune system fail to self-destruct and get out of the way as normal cells should, and can turn against the body’s own tissues, damaging joints and organs. No one yet understands why these autoimmune disorders occur, but this drug may offer a way to slow or prevent the damage caused by these misbehaving immune system cells, the authors say. "Our compound is more selective than current drugs," said lead author Gary D. Glick, a charter faculty member of the U-M Life Sciences Institute who is the Werner E. Bachmann Collegiate Professor of Chemistry and a professor of biological chemistry in the U-M Medical School. "The lupus treatments in use now just wreck your bone marrow." Current treatments suppress normal immune system function in general, leaving patients more vulnerable to infection. But Bz-423 acts selectively, triggering the self-destruct mechanism in just the immune system cells that are malfunctioning. The bone marrow, where new immune system cells are manufactured, is unharmed by the drug. In a study with genetically mutant mice that would normally experience high rates of kidney failure because of an auto-immune syndrome that models human lupus, treatment with Bz-423 significantly reduced the incidence of kidney damage and mortality. By the end of this study, 40 percent of the mice that were untreated died of kidney disease, but none of the treated mice died. Kidney failure is the leading cause of death for lupus patients, who number up to 1.4 million Americans according the Lupus Foundation of America. In the past 20 years, some 22,000 Americans have died from this disease. By comparison, rheumatoid arthritis affects 2.1 million Americans, mostly women. In this disease, the immune system attacks healthy joint tissue and causes inflammation and subsequent joint damage. The treated mice in this study showed fewer signs of joint damage associated with rheumatoid arthritis. The exact mechanism that makes the drug more effective against diseased immune cells has to do with the higher amount of reactive oxygen produced by the sick cells, says Glick. Normal immune B-cells and T-cells don’t have much reactive oxygen. But T-cells in lupus have surplus amounts of this "killer oxygen" and are also less able to detoxify it. The drug simply serves as a "kick in the back" to make these sick cells self-destruct as they should, Glick suspects. Glick plans to apply to the Food and Drug Administration for permission to test the compound in humans. The University of Michigan has applied for several patents on the medical and pharmacological properties of the compound and its molecular target. The research was funded by the National Institutes of Health and the U-M Multipurpose Arthritis and Musculoskeletal Diseases Center. The paper’s authors include Jeffrey J. Bednarski, an M.D. and Ph.D. student; Roscoe L. Warner, Ph.D., research investigator in pathology; Tharaknath Rao M.D., lecturer in Internal Medicine; Raymond L. Yung, M.D., Ph.D., assistant professor of internal medicine; Bruce C. Richardson, M.D., Ph.D., professor of internal medicine; Kent J. Johnson, M.D., professor of pathology; and Jonathan A. Ellman and Francesco Leonetti of the University of California-Berkeley, and Anthony Opipari, Jr. M.D., Ph.D., assistant professor of obstetrics and gynecology at U-M..
Gary D. Glick’s research interests:
www.umich.edu/~michchem/faculty/glick/

U-M Multipurpose Arthritis Center:
www.research.umich.edu/proposals/proposal_dev/UM_Resources/Arthritis.html

NIAID National Institute of Allergy and Infectious Diseases:
www.niaid.nih.gov/default.htm NIGMS National Institute of General Medical Sciences:
www.nigms.nih.gov

National Institute of Arthritis and Musculoskeletal and Skin Diseases:
www.niams.nih.gov
647-1842
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Nancy Ross-Flanigan, (734) 647-1853
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