LAB REPORT
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.
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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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