Pre-Clinical Summary

Mouse allergen challenge models are commonly used as predictors of clinical efficacy in asthma. In allergen-sensitized mice, aerosol administration of a mouse IL 4Rα-specific ASO resulted in dose-dependent pharmacological effects that correlated with antisense inhibition of IL-4Rα protein in lung cells. Once-weekly inhaled IL-4Rα ASO treatment suppressed allergen-induced airway hyper-responsiveness (AHR) to methacholine, airway eosinophilia and mucus production. Reduced expression of IL-4R following inhaled ASO treatment was associated with reduced levels of Th2 cytokines and chemokines and reduced expression of the epithelial mucin gene, Muc 5AC, a key component of mucus. Addition of inhaled IL-4Rα ASO to a suboptimal dose of inhaled budesonide in allergen challenged mice resulted in greater reductions in allergen-induced airway inflammation and hyperresponsiveness than either agent alone.

Treatment with an inhaled IL 4Rα as ASO was also effective in reducing airway eosinophilia, mucus overproduction and AHR in chronically challenged mice. The magnitude and quality of the IL 4Rα ASO effects were similar to those demonstrated by systemically administered Dexamethasone (a clinically proven corticosteroid) in chronically allergen challenged mice, with the added benefit of reduced numbers of airway neutrophils.

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