Cincinnati—University of Cincinnati (UC) College of Medicine
researchers announced today the successful genetic engineering of a
mouse that is resistant to asthma. Sponsored by the National Heart,
Lung, and Blood Institute of the National Institutes of Health, the
study results will appear in tomorrow's edition of the Journal of Biological Chemistry.
Dennis
W. McGraw, MD, assistant professor of internal medicine-pulmonary, and
Stephen B. Liggett, MD, professor of internal medicine and molecular
genetics and chief of Pulmonary and Critical Care Medicine, headed the
project. The goal was to alter the genetic structure of a mouse so that
it would not experience the closing of the airways or bronchospasm that
occurs in asthma. "We discovered that overexpressing this gene in a
genetically altered mouse prevented bronchospasm," explains Liggett.
"This finding is the first step toward a potential gene-based therapy
in humans."
Asthma is one of the most common chronic conditions
in the US, affecting an estimated 15 million people. It is caused by an
inflammation in the lung that constricts the smooth muscle surrounding
the bronchi. The result is an obstruction of airflow, which causes
wheezing and difficulty in breathing. "While stopping the inflammation
is an important component to curing asthma, a powerful treatment that
keeps the airways open would be a viable therapy," states McGraw.
Currently,
the best medications for opening the airways are beta-agonists. These
drugs attach to a receptor called the beta-2 adrenergic receptor and
relax the smooth muscle that surrounds the airways. The researchers
reasoned that increasing the number of these receptors in airway smooth
muscle could help keep the muscle in a relaxed state. To do this, they
genetically engineered mice to overexpress or produce more of the human
beta-2 receptor in the airway. When the engineered mice are mated, they
pass the altered gene to their offspring.
Researchers exposed the
genetically engineered mice to vapors that cause severe
bronchoconstriction in normal mice. The genetically altered mice showed
very little change in their breathing. McGraw noted, "The transgenic
mice breathed as if nothing unusual had happened. The normal mice
clearly had significant difficulty moving air. These results were
clearly visible to the naked eye, and subsequent careful measurements
of airflow have shown an incredible resistance to constriction in these
mice."
The results of this project support the idea of gene
therapy for asthma to keep the airways open. Conceivably, the
engineered DNA could be delivered by aerosol to the lungs, enabling the
appropriate cells to produce more receptor. "While many steps are
needed before human trials could be done, we are cautiously optimistic
that this is a viable approach."