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Cystic Fibrosis Mouse May Open Door to New Therapies

By Nancy Touchette

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Cystic Fibrosis
Mice and Rats

Despite the discovery nearly fifteen years ago of mutations in a gene that causes cystic fibrosis, scientists have been baffled by the disease. Although hundreds of mutations in the gene have been discovered in people with cystic fibrosis, it is unclear how these mutations lead to disease.

Progress has been slow in part because researchers have been unable to produce a suitable animal model of the disease. Even mice that are missing the cystic fibrosis gene do not develop the disease.

Now researchers at last have developed a mouse model of cystic fibrosis. The mice have a completely normal cystic fibrosis gene. However, a second gene, called SCNN1, that normally works with the cystic fibrosis gene to maintain salt balance in cells is overly active.

The mice experience most of the symptoms of cystic fibrosis in humans, including thick mucus secretions, chronic inflammation, and bacterial infections in the respiratory tract.

Researchers expect that the new mouse model will be most useful as a way to test potential therapies that might help improve lung function in people with the disease. And the research suggests that the second gene, SCNN1, is a possible target for new drugs.

“The field has been hampered by the lack of a good animal model of the disease,” says William Guggino, a longtime cystic fibrosis researcher at John Hopkins School of Medicine in Baltimore, Maryland.

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Guggino was vacationing with his family when the cloning of the gene, called CFTR, was announced in 1989.

“I turned to my wife and said ‘The study of cystic fibrosis is over. The gene has been cloned,’” recalls Guggino. “But everything about the CFTR gene has been much more complicated than we expected.”

In the new study, researchers show in mice that the overproduction of a sodium channel protein is enough to cause disease. This suggests that the abnormal loss of sodium from the respiratory tract is an important part of the disease process in humans.

“We show for the first time that the accelerated loss of sodium from the airways results in dehydration of airway surfaces,” says Marcus Mall of the University of North Carolina in Chapel Hill, lead author on the new study. The findings appear in Nature Medicine.

The CFTR gene makes a protein that acts as a channel to guide chloride ions into the fluid that bathes the respiratory tract. The chloride channel works in concert with the sodium channel to keep the sodium and chloride levels in balance.

Together, sodium and chloride form salt, or sodium chloride. Water flows in and out of the membranes lining the airways to keep the salt at a constant concentration.

“The cilia that line the airways and clear the mucus rely on a beating mechanism,” says Mall. “When there’s not enough fluid, they can’t function. Mucus plugs up the airway surfaces and they can’t clear out the bacteria.”

Cystic fibrosis patients have defects in the chloride channel and develop abnormally low levels of salt and fluid in the membranes that line the airways. As a result, they develop thick, sticky mucus that plugs up the lungs. This leads to inflammation, chronic infection, and ultimately death.

Attempts to find new drugs to treat patients with cystic fibrosis have mostly focused on molecules that can affect the chloride channel. But the new study suggests that drugs that affect the sodium channel might also help.

The sodium channel gives us another target for developing therapies,” says Guggino. “It might be possible to block this channel and do some good for patients with cystic fibrosis.”

Mall, M. et al. Increased airway epithelial Na+ absorption produces cystic fibrosis-like lung disease in mice. Nature Medicine Published online April 11, 2004.

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