December 18, 1998
Scientists have uncovered a possible new way to prevent asthma attacks by targeting an out-of-control chemical messenger that may be a basic biochemical cause of the disease.
The new finding, along with some previous studies, is setting off a race among several drug and biotechnology companies to develop new, more powerful drugs.
Asthma, an uncontrolled inflammation of the lungs that leads to severe constriction of the air passages, afflicts some 17 million Americans, and its incidence is growing. The Centers for Disease Control and Prevention estimates that asthma incidence has more than doubled since 1980, for reasons that aren't fully understood. Asthma-related hospitalizations also have increased 20% in recent years despite more aggressive treatment.
Most existing treatments have limitations -- they either merely target symptoms, or have the potential for long-term side effects by broadly suppressing the immune system. But the new finding in laboratory animals, to be reported Friday in the journal Science, brings scientists closer to understanding the disease's biological source.
Two reports -- one by scientists at Johns Hopkins School of Public Health in Maryland, the other by researchers at the University of California at San Francisco -- implicate an immune molecule called IL-13 as a key driver of the disease. Using an experimental drug from American Home Products Corp. in tests on laboratory animals, the researchers showed that blocking IL-13 completely prevents asthma attacks.
The Science reports are the latest in a series of major studies suggesting that chemical messengers called interleukins are central biological triggers of asthma. Interleukins such as IL-13 (short for interleukin-13) are chemical messengers that are normally released in the presence of a foreign invader, and help organize the body's immune system response. They trigger the release of other immune molecules that in turn cause inflammation.
Deadly Attacks
Normally, the defensive action of interleukins is crucial to defending the body from infection. In the lungs of asthmatics, for reasons that aren't completely understood, various interleukins are present at inappropriately high levels. They generate a massive and inappropriate lung inflammation in response to the slightest irritant, such as dust, pollution or even stress, resulting in asthma attacks that can be deadly.
Now several drug and biotechnology companies are rushing to develop medications based on blocking interleukins. Genetics Institute, a biotechnology unit of American Home Products, is already racing to test its IL-13 blocker and says human tests could begin in a year or so. Meanwhile, Immunex Corp., of Seattle, is in early human testing of a similar drug that blocks a closely related substance called IL-4. Schering-Plough Corp., Madison, N.J., and SmithKline Beecham PLC of the United Kingdom also have drugs in early human testing that target a third critical immune molecule, IL-5, which seems to be important in asthma cases related to allergies.
If proven safe and effective in human tests, these drugs might be given as inhalants or injections just once a week or less, unlike existing drugs, which are administered daily. They may also be able to reverse some of the lung inflammation that causes asthma attacks. Drugs based on interleukins "will be more effective than existing agents, because they target molecules closer to the causes of the disease," predicts Lanny Rosenwasser, an asthma researcher at the National Jewish Medical and Research Center in Denver. Researchers cautioned that all the new drugs are in early stages of development, and need to undergo several more years of human testing.
Top scientists say no single approach is likely to cure asthma because the disease is too complicated. Instead, they say, various combinations of drugs may be given together for effective control of the disease, in the same way that drug cocktails are used to suppress the HIV virus in AIDS patients.
Ten or 15 years from now, there will be several new asthma treatments available, each of which narrowly targets a specific immune molecule important in asthma, predicts Anthony Rebuck, vice president for pulmonary disease and diabetes research and development at SmithKline. Instead of all asthmatics being prescribed inhaled steroids, the standard preventative treatment today, patients will get their DNA or urine tested before treatment, he says. "This will tell you not only what type of asthma you have, but what type of treatment is ideal for your type of asthma."
Slow Progress
Scientists have been working for decades to identify the basic biochemical and genetic defects that cause asthma. But until recently, progress was slow because it turns out that there is no single molecule or gene that causes the disease. Instead, a complex interaction of numerous malfunctioning immune molecules leads patients to develop the disease, often beginning in early childhood.
In some patients, asthma seems to be triggered mainly by allergies; in others it comes on after the stress of heavy exercise.
Moreover, some patients are thought to have yet-to-be-identified gene patterns that make them more vulnerable to the disease. In the last decade, scientists have found evidence that IL-4 and IL-5 are two of the molecules that can play key roles. The new reports in Science indicate that IL-13 may be equally important.
Researchers at American Home's Genetics Institute weren't even focusing on asthma when they stumbled onto the tie between IL-13 and the disease. Instead, they were working on identifying therapeutically useful new genes by making genetically engineered copies of as many new genes and proteins as possible.
Researcher Debra Donaldson happened to clone a protein that turned out to be the receptor for IL-13. Receptors are proteins on the surface of cells that bind to and receive biochemical messages from signaling molecules such as IL-13. Thus the IL-13 receptor receives messages from IL-13. But Dr. Donaldson initially didn't know what diseases the IL-13 receptor might be involved in.
At the same time, asthma researchers Marsha Wills-Karp at Johns Hopkins and David Corry at the University of California at San Francisco and their colleagues were independently investigating IL-13's role in asthma. They noticed that IL-13 was biochemically similar to IL-4, and suspected it might be acting as an "evil twin" to IL-4, wreaking havoc in the lungs of asthmatics.
They teamed up with Dr. Donaldson, who provided an experimental drug derived from the IL-13 receptor that soaks up and disarms IL-13 present in the lungs, preventing it from causing inflammation and other damage. When this experimental drug was given to laboratory mice with induced asthma, symptoms of asthma such as constricted airways and mucous in the lungs virtually disappeared, according to the two reports in Science.
Dr. Patrick Gage, who is president for research at American Home's main pharmaceutical unit, said his company is racing to develop an inhaled version of its IL-13 blocking drug suitable to enter human tests.
Pulmonology
