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Feb 10, 2011
 |  BC Innovations  |  Targets & Mechanisms

Getting a GRP on asthma

Researchers at the Duke University School of Medicine have shown thata small molecule blocker of gastrin-releasing peptide, originally identified as a tumor growth inhibitor by researchers at the National Cancer Institute, attenuates multiple parameters of asthma with an overall effect that is stronger and longer lasting than that of corticosteroids.1 The compound was effective in two validated mouse asthmamodels, which is uncommon among drug classes marketed for the indication. The findings suggest that the peptide could be a new target for asthma, and the group is now working to elucidate the mechanism of its candidatecompound.

Gastrin-releasing peptide (GRP) regulates normal fetal lung development2,3 but also has bronchoconstrictive effects. Excessive levels of GRP have been associated with various inflammatory lung conditions in humans, including bronchopulmonary dysplasia in infants.4,5

Because about 50% of infants with bronchopulmonary dysplasia develop asthma later in life,6 a Duke group led by Mary Sunday hypothesized that blocking GRP signaling could prevent clinical manifestations of asthma (see "A model of the GRP signaling cascade in asthma").

In mouse models of asthma triggered by either air pollution or allergens, prophylactic injections of a small molecule GRP blocker decreased multiple parameters of asthma compared with those in control animals.

The blocker, dubbed 77427,showed stronger effects than the corticosteroid dexamethasone across three key efficacy measures: airway hyperresponsiveness, inflammatory cell counts and cytokine levels in bronchoalveolar lavage fluid. The beneficial effects of 77427 persisted for at least three days.

Results were published in the Proceedings of the National Academy of Sciences.

"Our small molecule brought airway hyperresponsiveness back to baseline in validated models of the two major types of asthma," said Sunday, who is corresponding author on the paper.

Sunday, a professor...

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