Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

New compound holds promise for lupus and related diseases

16.10.2002


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), researchers at the University of Michigan and the University of California-Berkeley have found.



Their research, described in the Oct. 16 issue of the Journal of Clinical Investigation, also reveals the novel mechanism by which the compound works, a discovery that could lead to safer and more effective new drugs for managing lupus and other autoimmune disorders.

"The best available therapies for lupus haven’t changed for many, many years," says U-M’s Gary D. Glick, Ph.D., one of the lead authors on the study. "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 inflammation---the major cause of illness and death in lupus patients---are 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, 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 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.

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 over 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 Anthony Opipari, M.D., Ph.D., assistant professor of obstetrics and gynecology and a lead author of the study.

In an attempt to find new drugs for treating lupus, Glick and his co-workers screened a collection of benzodiazepines to identify any that killed immune cells. They chose benzodiazepines because unlike most cytotoxic drugs, these compounds do not damage DNA or interfere with cell metabolism. "We suspected that any benzodiazepines that were capable of killing cells would possess unique modes of action and perhaps be better at targeting disease-causing cells," says Glick.

In a series of experiments using cultured B cells (immune cells that make antibodies), the researchers found that Bz-423 targets a protein inside the cells’ mitochondria. To test the effectiveness of Bz-423, Glick and his team then gave the compound to mice with lupus. At the end of the treatment period, 60% of untreated mice had lupus-related kidney disease, compared to 16% of treated mice. The treated mice showed none of the side effects caused by currently available lupus drugs.

"The results suggest that Bz-423, when administered appropriately, may have a significant therapeutic potential for lupus," says Glick. There is also 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, according to Opipari.

"This paper illustrates the wonderful opportunities there are for chemists, such as Drs. Glick and Ellman, who are willing to venture beyond the lab and apply their skills to significant problems in human health," says John M. Schwab, a program director at the National Institute of General Medical Sciences, which supported the research. "At the same time, it shows that clinicians and patients can benefit by including a chemical or molecular perspective in thinking about how to combat a complex, life-threatening disease."

Working with a compound that belongs to one of the most well-studied families of drugs---the benzodiazepines---is remarkably helpful in moving Bz-423 into clinical trials, because so much is already known about chemical and pharmacological properties of that group, Glick says. Although Bz-423 is structurally similar to anti-anxiety drugs such as Valium and Xanax, subtle structural differences give it some advantages. For example, Bz-423 does not cause drowsiness or lead to addiction, says Glick.

After completing additional research on Bz-423, 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.


In addition to Glick and Opipari, 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, Ph.D., research investigator in pathology; 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. The research was funded by the National Institutes of Health and the U-M Multipurpose Arthritis Center.

Additional Contact:
Nancy Ross-Flanigan, rossflan@umich.edu, (734) 647-1853


Sally Pobojewski | EurekAlert!

More articles from Health and Medicine:

nachricht Researchers release the brakes on the immune system
18.10.2017 | Rheinische Friedrich-Wilhelms-Universität Bonn

nachricht Norovirus evades immune system by hiding out in rare gut cells
12.10.2017 | University of Pennsylvania School of Medicine

All articles from Health and Medicine >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Neutron star merger directly observed for the first time

University of Maryland researchers contribute to historic detection of gravitational waves and light created by event

On August 17, 2017, at 12:41:04 UTC, scientists made the first direct observation of a merger between two neutron stars--the dense, collapsed cores that remain...

Im Focus: Breaking: the first light from two neutron stars merging

Seven new papers describe the first-ever detection of light from a gravitational wave source. The event, caused by two neutron stars colliding and merging together, was dubbed GW170817 because it sent ripples through space-time that reached Earth on 2017 August 17. Around the world, hundreds of excited astronomers mobilized quickly and were able to observe the event using numerous telescopes, providing a wealth of new data.

Previous detections of gravitational waves have all involved the merger of two black holes, a feat that won the 2017 Nobel Prize in Physics earlier this month....

Im Focus: Smart sensors for efficient processes

Material defects in end products can quickly result in failures in many areas of industry, and have a massive impact on the safe use of their products. This is why, in the field of quality assurance, intelligent, nondestructive sensor systems play a key role. They allow testing components and parts in a rapid and cost-efficient manner without destroying the actual product or changing its surface. Experts from the Fraunhofer IZFP in Saarbrücken will be presenting two exhibits at the Blechexpo in Stuttgart from 7–10 November 2017 that allow fast, reliable, and automated characterization of materials and detection of defects (Hall 5, Booth 5306).

When quality testing uses time-consuming destructive test methods, it can result in enormous costs due to damaging or destroying the products. And given that...

Im Focus: Cold molecules on collision course

Using a new cooling technique MPQ scientists succeed at observing collisions in a dense beam of cold and slow dipolar molecules.

How do chemical reactions proceed at extremely low temperatures? The answer requires the investigation of molecular samples that are cold, dense, and slow at...

Im Focus: Shrinking the proton again!

Scientists from the Max Planck Institute of Quantum Optics, using high precision laser spectroscopy of atomic hydrogen, confirm the surprisingly small value of the proton radius determined from muonic hydrogen.

It was one of the breakthroughs of the year 2010: Laser spectroscopy of muonic hydrogen resulted in a value for the proton charge radius that was significantly...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

ASEAN Member States discuss the future role of renewable energy

17.10.2017 | Event News

World Health Summit 2017: International experts set the course for the future of Global Health

10.10.2017 | Event News

Climate Engineering Conference 2017 Opens in Berlin

10.10.2017 | Event News

 
Latest News

Terahertz spectroscopy goes nano

20.10.2017 | Information Technology

Strange but true: Turning a material upside down can sometimes make it softer

20.10.2017 | Materials Sciences

NRL clarifies valley polarization for electronic and optoelectronic technologies

20.10.2017 | Interdisciplinary Research

VideoLinks
B2B-VideoLinks
More VideoLinks >>>