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.