Asthma

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What do current treatments for Asthma do?

 The primary treatments for asthma are inhaled steroids that reduce the overall inflammation, and long-acting beta-2-adrenergic receptor agonists that reduce acute bronchoconstriction events. While steroids do treat the inflammation that underlies the disease, they are not well tolerated as a long-term treatment.  Beta-agonists, do not treat the underlying disease, only the acute symptoms, and patients can become less responsive to even the acute relief benefits with long-term treatment. For patients who are not well-controlled with steroid treatment, injection of IgE-titrating antibodies have been effective but they do not  treat neutrophilic asthma such as is characteristic of some environmental pathogens.Therefore, there is an unmet need for alternative treatments for asthma.

PAR-2 Technology

How PAR-2 affects asthma

PAR-2 expressed on airway epithelial cells mediates the initial inflammatory responses to proteases, released from common household pathogens, including production of cytokines and chemokines; mast cell degranulation; impaired epithelial barrier function and mucus production. Locally released proteases can activate PAR-2 on inflammatory cells (eosinophils, lymphocytes and neutrophils), to enhance chemokine-induced recruitment to the airway and exacerbating the inflammation. Ultimately, thickening of the bronchial epithelium and secretion of mucus causes obstruction of the airways and bronchoconstriction.

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What is our approach to Asthma involving PAR-2?

  Previous attempts to pursue PAR-2 as a therapeutic target for asthma have been difficult because its activation also leads to release of Prostaglandin E2 (PGE2) from epithelial cells, which play a protective role in the airway by promoting smooth muscle relaxation and subsequent bronchodilation. In Alternaria and Cockroach-induced asthma, as well as PAR-2 induced exacerbation of Ova-induced asthma, the inflammatory phenotype is dependent upon signaling through a protein called beta-arrestin, while the protective bronchodilation occurs through a G-protein-dependent pathway. Beta-arrestin-2 recruitment to PAR-2 is required for production of inflammatory interleukins (IL-4, IL-6 and IL-13), mucus production and bronchoconstriction. Expression of beta-arrestin in leukocytes is required for both PAR-2 and chemokine-induced recruitment to the airways. PGE2 production is dependent upon G-protein, but not arrestin signaling.  Our approach exploits these distinct signaling pathways to develop PAR-2 antagonists that target the beta-arrestin pathway for the treatment of asthma.

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