Nature Biotechnology
18, IT10 - IT11 (2000)
doi:10.1038/80042
AsthmaWith asthma cases on the rise, a better understanding of the disease
on the molecular and systems levels promises more efficacious treatments.
Asthma is a chronic lung disease where inhalation and exhalation are obstructed
by the production of excess mucus and the swelling of the airway membranes,
giving rise to coughing and wheezing. To non-specialists, these same symptoms
may be confused with an infection. There is, however, a significant allergic
component to asthma—typical triggers include house-dust mites, molds,
pollen, and smoke.
Asthma needs to be treated constantly, and its burden on society is significant.
More than 17 million people are affected currently in the United States alone,
of which almost 5 million are under the age of 18. The prevalence of the disease
increased 75% in the period from 1980−1994, and the disease causes more
than 5,300 deaths each year, with morbidity rates among inner-city patients
on the rise. The financial burden of the disease is staggering; in the United
States, costs reach almost $10 billion annually, with another $3 billion in
indirect costs associated with loss of productivity1. Because
of its impact, asthma is the subject of major research interest among academic
centers and and pharmaceutical companies worldwide.
Historical perspective
Attempts to manage, understand, and treat asthma have a long history. Even
in the early 1960s, aerosols containing small peptides such as serotonin and
bradykinin were used to treat the disease2, and lifestyle and
nutrition suggestions were also prevalent3. In the mid-1960s,
steroids began to be introduced, with the increasing use of injectable formulations4. By that time, asthma was recognized to have a significant allergic
component, even though the precise triggers of the disease were poorly characterized5. Nevertheless, work had already demonstrated a role in the disease
for basophil leukocytes, for example6. By the early 1970s, corticosteroids
were a major treatment choice, and their long-term use in depot form was being
assessed7. At the same time, new treatment options were emerging,
such as selective  -adrenergic receptor stimulants8, and
there were efforts to optimize oral formulations of medicines, such as salbutamol
for children9. Newer bronchodilators were also being introduced,
such as hexoprenaline10, and combination therapies involving
some of the newer medicines, such as disodium cromoglycate and prednisone11 were assessed in the clinic. At the beginning of the 1980s, the
underlying involvment of the immune system was sufficiently clear to lead
to initial discussions of potential immunotherapies and vaccines against asthma12.
Together with the arrival of new medicines, traditional and alternative
medicine, such as acupuncture, were also explored13. In the
past decade, efforts have focused on understanding the disease at the level
of specific protein expression, and several studies have reported a variety
of interleukins (ILs), for example, IL-5, expressed specifically in bronchial
tissue of asthmatic sufferers14. These studies have been complemented
by others focusing on the identification of specific genes linked to the disease,
and putative links with the 2-adrenoreceptor were reported15.
More recently, longer-acting medicines have been described and analyzed, such
as the bronchodilator salmetarol16 and tiotropium bromide, a
long-acting muscarinic antagonist17.
Current state
Although a great deal has been discovered and described about asthma at
the molecular and systems levels, academic and corporate research continues
to broaden the understanding of the various parameters of the disease. Both
disease-related protein expression and also identification and characterization
of genetic predispositions are the subject of intense work, whose aim ultimately
is to validate better drug targets and develop even better leads.
For example, although inflammation of the airway wall is a significant
physiological response in asthma, debate is ongoing about the exact cytokines
and immune system cells involved. On the basis of positional cloning and animal
models, IL-9 has been proposed as a candidate gene for asthma. A recent report
supported this further by finding that IL-9 specific receptor expression was
detected in samples of airways from asthmatic patients, but not from healthy
controls, indicating a putative role for IL-9 in the mechanism of disease18.
In addition to IL-9's connection, the hunt for asthma genes is very
active at present. For example, a recent report describes significant linkage
analysis evidence based on genome-wide searching that correlated mite-sensitive
childhood asthma to chromosome 5q31-q33 near the IL-12 B locus in Japanese
families19. This correlation is found in other population groupings
as well.
Finally, the interest of the pharmaceutical and biotechnology industries
in the disease is very significant, as demonstrated by the variety of programs
and approaches shown in Table 1.
Industry challenges
The full spectrum of analytical approaches is being used to characterize
asthma at the molecular level, including epidemiology studies of families
over several generations, twin studies, genome-wide scans and candidate-gene
efforts, in humans and also in animal models of the disease. To date, all
of these approaches are revealing not one clear candidate, but multiple regions
in both the human and mouse genomes that correlate strongly with the disease,
and may thus contain specific target genes20. This is a significant
challenge, as it suggests that asthma is a multi-factorial disease with multiple
potential drug targets whose therapeutic potential remains to be resolved.
This is both good and bad. With more potential candidates, there are more
medicines possible, which will work in different ways and thus cover a broader
percentage of the population; however, it will take time to characterize properly
all of these potential targets and find the right ones to pursue further.
Another major challenge is that the understanding of actual cell physiology
in asthma, which will lead to the identification of better target molecules
and thus better drugs, is still unclear and very much under intense investigation.
For example, the airway smooth muscle cell, which contracts or relaxes depending
on the state of different signal transduction pathways, is a key cell governing
the diameter of the human airway. Histamine and acetylcholine, which are released
during an asthma attack, induce contraction by activating phospholipase C,
which releases inositol 1,4,5-triphosphate, causes the increase of intracellular
calcium, and thus induces muscle contraction. The cells relax mainly when
adenylyl cyclase-coupled receptors such as the 2-adrenoreceptor are
stimulated, for example by 2-adrenoreceptor agonist drugs, causing the
increase inside the cell of cyclic adenosine monophosphate, which itself causes
the efflux of calcium from the cell, and thus relaxation of the muscle. The
contraction/relaxation pathways also have complex cross-talk between them,
which ultimately means that the state of the airway muscle cell is very carefully
controlled. These factors and mechanisms are still being characterized and
are not fully understood at the signal transduction level. Once they are,
better drugs will be possible21.
Finally, a constant challenge to the industry is that current drugs that
often have to be used chronically have side effects over the period of their
use. For example, there is ongoing debate about the link between corticosteroids,
which are very valuable anti-inflammatory and immunosuppressive agents, and
their correlation with increased risk of osteoporosis after long-term exposure22. There is ongoing research in this area focusing on validating
or discounting these risks, developing appropriate guidelines for these drugs,
and balancing the need for their short and medium-term use with their long-term
risk potential.
Future directions
In addition to advances in genetic mapping of the disease and generation
of new medicines, the future will see major advances against asthma as a result
of our increasing understanding of all facets of this disease. For example,
in severe asthma, mucosal neovascularization and bronchial angiogenesis are
a significant feature of the remodeling of the airways that occurs in severe
forms of the disease. This remodeling is only now beginning to be extensively
characterized23. It is, however, a major symptom and will no
doubt lead to the identification of new targets and development of new medicines.
Basic pharmacological principles will also be increasingly applied to asthma
medicines. For example, albuterol is a major asthma medication that is actually
formulated as a racemate, as are most drugs for most diseases. The drug consists
of a 50:50 mixture of the (R)- and (S)-stereoisomers. A recent
sudy comparing racemic albuterol with the single isomer version (R)-albuterol
(levalbuterol) found that a lower dose of levalbuterol is as effective as
a higher dose of racemic albuterol and had less side effects24.
This suggests that increased understanding of the impact of stereoisomer forms
of medications will lead to better medicines with fewer side effects.
Finally, the future promises progress on deciphering the effect of the
environment, especially coupled to specific population prevalence levels—including
factors such as unhealthy work environments, prior exposure to potential asthma
triggers, and social factors such as income-levels and inner city homes—all
of which are linked to increasing risk for the disease25.
Conclusions
Asthma is a manageable disease with a major societal burden. As a result,
it is the focus of massive academic and industry efforts to understand it
at the genetic, molecular, cellular, whole organism and societal levels. Significant
recent advances on all fronts suggest that significant new and better treatments
are on their way.
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