Johns Hopkins Gazette | February 16, 2009
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The newspaper of The Johns Hopkins University February 16, 2009 | Vol. 38 No. 22
Old Meds Hold Promise As Therapy for Autoimmune Diseases

By Maryalice Yakutchik
Johns Hopkins Medicine

A century-old drug that failed in its original intent to treat tuberculosis but has worked well as an antileprosy medicine now holds new promise as a potential therapy for multiple sclerosis and other autoimmune diseases.

"We never expected that an old antibiotic would hit this target that has been implicated in multiple sclerosis, psoriasis and type 1 diabetes," said Johns Hopkins pharmacologist Jun O. Liu. "People have been working for years and spending tens of millions of dollars on developing a drug to inhibit a specific molecular target involved in these diseases, and here we have a safe, known drug that hits that target." The target is the Kv1.3 potassium channel.

The finding about clofazimine, a synthetic compound made in the 1890s, is reported in Public Library of Science by Johns Hopkins University researchers, who uncovered the drug's latest potential during an ongoing and exhaustive screening of FDA-approved drugs designed to identify new uses for them. The team was specifically hunting for immune-system control agents within the Johns Hopkins Drug Library, a collection assembled over the past seven years by Liu and colleagues of more than 3,000 drugs in pharmacies or being tested in phase II clinical trials.

The scientists said they were surprised to discover that clofazimine interferes with a molecular pathway important in orchestrating the human body's immune response.

"Until now, clofazimine's presumed target was not human cells but bacteria," said Liu, a professor of pharmacology and molecular sciences in the School of Medicine. "But we discovered the drug has a tremendous effect on human immune cells that are heavily involved in both the initiation and execution of an effective immune response."

More specifically, Liu's team sought drugs that stop the molecular signaling pathway that leads from the surface of an immune-system cell to the cell's interior, where the signal turns on genes important in activating the immune response. In autoimmune diseases, a person's own white blood cells, meant to fight infection or disease, are misguided to the target and attack the body's own cells, damaging or destroying them.

To search for such compounds, the team first engineered cells to mimic an immune cell's natural signaling pathway, a complex and circuitous route from the cell surface to the genetic switch inside. They then subjected these specialized cells to the Drug Library, one at a time, and identified more than 200 hits — drugs that inhibited the signaling system significantly, by more than 50 percent.

When they compared the potency of the 200 with each other, "clofazimine was the hit with the highest inhibitory activity," Liu said.

Next, by systematically studying the multistep signaling process, the researchers pinpointed clofazimine's molecular target, a protein "pore" called ion channel Kv1.3, which plays an essential role in the complicated signaling process. One of the key steps involved in turning on the immune response is the prolonged accumulation of calcium inside of immune cells, Liu said. When the researchers stimulated an immune cell, setting the signaling event in motion, they noticed that lots of calcium flushed into the cell and lingered there. However, when they pretreated the immune cells with clofazimine, the calcium rush was much less, and it didn't hang around as long.

"This let us conclude that clofazimine was blocking the calcium influx into the immune cells," Liu said. "Without enough calcium getting inside a cell, the signaling pathway that turns on the immune response was short-circuited." The Johns Hopkins group also showed that clofazimine tamps down the presence of free calcium in immune cells by disrupting a potassium channel. The combined effect is to shut down a signaling pathway involved in autoimmune disease.

In addition to Liu, authors of this paper are Yunzhao R. Ren, Fan Pan, Curtis R. Chong, Jing Xu, Yongjun Dang and Jin Zhang, all of Johns Hopkins; Reinhold Penner, Suhel Parvez and Andrea Fleig, all of the University of Hawaii; and Hongsi Jiang, of Northwestern University.


Related Web sites

Jun O. Liu
'Public Library of Science'


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