Sunday, June 15, 2003

Local scientists zeroing in on asthma

Hundreds of genes involved, adding complexity - and hope

By Tim Bonfield
The Cincinnati Enquirer

For years, researchers knew that asthma was a complicated disease.

But now, a massive genetic analysis in mice that was led by experts at Cincinnati Children's Hospital Medical Center shows that the breathing disorder is much more complicated than thought.

Not one, not 10 or 20, but 291 different genes are associated with asthma, according to the study, released today and to be published in the July issue of the Journal of Clinical Investigation.

"We are literally defining the asthma genome, which will have tremendous long-term implications for research," said the study's senior author Dr. Marc Rothenberg, director of allergy and immunology at Cincinnati Children's.

Asthma is a common and growing illness that affects more than 17 million Americans, including more than 4.8 million children. Asthma rates in children under 5 grew more than 160 percent from 1980 to 1994, according to Cincinnati Children's.

In Greater Cincinnati, about 194,000 people have asthma, and nearly one-third reported in a 1998 survey that the condition caused them to miss school or work that year, according to the Respiratory Institute, an arm of the drug-maker GlaxoSmithKline.

In addition to senior author Dr. Rothenberg, the two-year-long asthma study was produced by Drs. Nives Zimmerman and Nina King at Cincinnati Children's and with collaboration from researchers in Canada, Australia and at Pennsylvania State University.

"This is a very interesting finding, but it's still too early to say how this is going to affect people," said Jodi Giammarco, executive director of the Canada-based Childhood Asthma Foundation. "If it is this complicated, then there's a lot of work to be done to find a cure."

More than half of the 291 mouse genes reported by the study have never been linked with asthma before, which offers the medical world a bounty of new ways to study and potentially treat the disease, Rothenberg said. Already, Cincinnati Children's researchers believe one of the newly linked genes - called arginase - may play a powerful role in asthma and may serve as a new target for developing better treatments.

Rethinking asthma

The Cincinnati Children's study was based on studies of mouse DNA as a model of human DNA. The arginase findings were further verified with comparisons to human DNA drawn from samples of asthmatic lung tissue.

In humans, the number of genes involved may not be exactly 291, but it likely will be close, Rothenberg said. And with so many genes involved, experts may begin rethinking the entire concept of asthma.

Rather than one distinct disease, asthma may become an umbrella term like cancer, which actually describes hundreds of kinds of tumors.

"This finding could allow us to begin stratifying people with asthma," Rothenberg said. "Two wheezing people coming into the doctor's office may look the same in lung function tests, but what's going on at the cellular level could be completely different.

"One patient might respond well to prednisone. Another might respond to Singulair. Someday, we may be able to develop a genetic fingerprint of a person's asthma and be able to figure out exactly what to do for that individual."

A new target for research

Arginase is just one of the 291 genes identified in the Children's Hospital study, but it appears important because it was found well "upstream" in the flow of biological processes that lead to asthma.

Activation of arginase gene appears to be involved in multiple pathways researchers believe are critical to causing asthma symptoms.

Specifically, turning on the arginase gene - such as by exposing the lung to an allergy-causing substance - causes the body to produce argenine, an amino acid that plays multiple roles in the body including a useful role in liver function.

But in the lungs of a person with asthma, the substance breaks down into four different by-products that can cause airway contraction, airway inflammation and excess mucus production.

"Arginase was never identified before as having any role in asthma," Rothenberg said.

Much more study must be done to test the arginase theory. But experts hope to find or make a drug that blocks the arginase gene activity in the lungs, without causing serious harm in the liver or some other body system. If successful, such a drug could become a more powerful treatment for asthma than antihistamines and steroids used now to control symptoms.

"If you have asthma, you can take all the antihistamines you want but it won't be a cure, because all you're doing is blocking one of the last steps in the asthmatic reaction. To cure the disease, you have to be more upstream," Rothenberg said.

Steroids appear to have more of an upstream effect than antihistamines, but they also come with strong side effects in some people. No one knows yet what kind of side effects might occur from blocking arginase.

The advantage in this case however, is that much more information about those potential risks can be generated much faster than in years past. The same DNA chip technology that helped spot arginase also can be used to see how every part of the human genome reacts when and if a drug is developed to block arginase.

Cincinnati Children's already has a $1 million grant from the National Institutes of Health to continue studying the role arginase plays in asthma.

If the work bears fruit, powerful new treatments could be available within five to 10 years.



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