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."