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Sep 18, 2012

Asthma: Single Target, Double Blow

  • A recently identified calcium activated chloride channel (CaCC) in the airway surface epithelium and airway smooth muscle (ASM) cells of asthma patients could represent a target for reducing the excess mucus production and ASM hyperresponsiveness that characterize asthma attacks, researchers claim. Using transcription profiling of primary human cells, immunohistochemistry, and mouse models, a Howard Hughes Medical Institutes-led team has shown that epithelial expression of the CaCC TMEM16A is upregulated in asthma patients, and that blocking the channel using small molecule inhibitors negatively regulates mucin secretion and ASM contraction.

    Having demonstrated that production of TMEM16A is increased in the airway epithelial cells and secretory cells of both human asthmatics and mouse models of the disorder, Jason R. Rock, Ph.D., and colleagues carried out a high-throughput screen to identify potential inhibitors of the transmembrane protein. The most promising candidates included hexachlorophene, dichlorphen, which is used as a veterinal anticestodal, and benzbromarone, which has been used clinically to raise gout.

    Further in vitro studies using benzbromarone confirmed that the drug blocked mucus production by secretory cells in vitro, and also inhibited the contraction of isolated human bronchi in response to methacholine, a synthetic choline ester that is commonly used in a bronchial challenge tests to diagnose bronchial hyperreactivity in asthma and COPD.

    The potential thus exists to address two major factors associated with asthma by blocking a single target, the investigators report in their published paper in PNAS. “TMEM16A-CaCC blockers, including those identified here, may positively impact multiple causes of asthma symptoms.”

    Dr. Rock’s team is currently carrying out preclinical development of the small molecule compounds with a view to potential clinical trials. “At present, I am optimistic,” Dr. Rock says. “This could be a major advance to help asthma patients.”

    The Howard Hughes team and collaborators describe their work in a paper titled “Calcium-activated chloride channel TMEM16A modulates mucin secretion and airway smooth muscle contraction.” 



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