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SEPTEMBER 23, 2004
By Catherine Arnst Asthma Research Draws a Fresh Breath Study of a rare white blood cell's role in the disease had been all but abandoned, but fresh data point to its potential as a treatment Asthma is one of the most common chronic diseases, with more than 100 million sufferers worldwide. It's also one of the trickiest. As many as 150 different genes are involved in the development of this often-debilitating respiratory disease, which goes a long way toward explaining why countless potential therapies have been tested and abandoned. Patients have few choices beyond variations of the same problematic bronchodilators and steroids used a generation ago. However, some significant new research indicates that at least one avenue of attack that has been on the back burner may deserve a second look. Two new studies, reported in the Sept. 17 issue of the journal Science, found that one of the least common white blood cells, called eosinophils, play a key role in causing the inflammation in the airways that precedes asthma attacks. These studies have stirred up a lot of interest among asthma researchers because they directly contradict an important study published four years ago in The Lancet. That study, which was the first to try blocking eosinophils in humans, concluded that the cells had little or no role in causing the disease. At that point, drugmakers that had been pursuing anti-eosinophil therapies turned their efforts elsewhere. VICIOUS CYCLE. "The earlier study really threw off the enthusiasm in terms of drug development," says Marsha Wills-Karp, director of immunobiology at Cincinnati Children's Hospital Medical Center and co-author of a Science editorial on the new research. "These current studies may revive interest in targeting these pathways." Eosinophils, first discovered more than 100 years ago, have long puzzled researchers. They likely evolved to fight off internal parasites, a problem rarely found in the developed world. Asthma, though, has become a huge burden for industrialized countries. Its incidence -- and even more worrisome, its death rate -- has been steadily climbing for more than two decades, for no known reason. The chronic inflammatory disorder is caused by a hypersensitive immune system that vastly overreacts to any of a number of triggers, ranging from dust and pollen to viruses to changes in the weather. The white blood cells spew out inflammatory signals, causing the airways to swell up and produce excess mucus, which makes it difficult for the sufferer to breathe. Over time, these asthma attacks can damage the lungs, prompting scarring and tissue damage that make it even more difficult to withstand future attacks -- a vicious cycle that can lead to death if not monitored properly. Large numbers of eosinophils are found in the airways during these asthma attacks. But the Lancet study found that reducing the number of these enigmatic cells had no effect on airway restriction and mucus production. LONG-TERM IMPORTANCE. The Science studies may be more reliable, however, because they used mice that were genetically engineered to produce no eosinophils. The two teams of researchers, from Children's Hospital in Boston and the Mayo Clinic in Scottsdale, Ariz., attempted to induce asthma attacks in the mice. In the Mayo study, the mice developed no symptoms, a clear victory. In the Boston study, the mice did suffer from bronchial spasms and mucus production. However, there was no long-term damage to the lungs. Wills-Karp hypothesizes that the two studies had different outcomes because the mice were created in different ways. The Boston mice may have had a few eosinophils, and these cells could be so powerful that even a small number would be enough to induce asthma's short-term effects, though not the long-term lung damage. That could explain why blocking these cells in humans has done little good. Just a handful of cells could do a lot of harm, so they would all need to be knocked out -- a tough job for any drug. Dr. Craig Gerard, chief of the pulmonary division at the Children's Hospital in Boston, believes his hospital's mice may point to a role for anti-eosinophil drugs in long-term treatment rather than prevention of acute asthma attacks. "It's much more popular to study acute asthma, but chronic asthma leads to scar formation in the bronchial tubes and swelling of the smooth muscle," says Gerard. "Those reactions aren't at all affected by current treatments and may be more important to treat for the long run." LOW PRIORITY. Currently, few drug candidates target eosinophils for any reason. Over the years, several companies have developed antibodies that block interleukin-5 (IL-5), one of a family of blood proteins called cytokines that control inflammation. IL-5 specifically directs the creation of eosinophils. The whole cytokine approach, however, was thrown into question after Nuvance, a once-promising asthma medicine from Immunex Corp. that blocked interleukin-4, failed in mid-stage trials. The main IL-5 drug now in development, GlaxoSmithKline's (GSK ) mepolizumab, has been in Phase II trials against asthma since 1998 -- a sign that it's not a top priority. A Glaxo spokesman says the outfit is more interested in developing the drug as a treatment for atopic dermatitis. Still, "these drugs could be resurrected if someone could figure out the right trial for testing them," suggests Gerard. "We may have been asking the wrong questions before." Coming up with the right questions -- and the right mouse models -- is often one of the toughest challenges in science. And as these latest studies of eosinophils have shown, it's often worthwhile to recheck the answers.  Arnst is a senior writer for BusinessWeek Edited by Patricia O'Connell
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