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Anti-Inflammatory Activity of Inhaled IL-4 Receptor- Antisense Oligonucleotide in Mice

Departments of Clinical Development, Pharmacokinetics, and Antisense Drug Discovery, Isis Pharmaceuticals, Carlsbad, California

Correspondence and requests for reprints should be addressed to James G. Karras, Ph.D., Department of Clinical Development, Isis Pharmaceuticals, 1896 Rutherford Road, Carlsbad, CA 92008. E-mail: jkarras{at}isisph.com

The Th2 cytokines IL-4 and IL-13 mediate allergic pulmonary inflammation and airways hyperreactivity (AHR) in asthma models through signaling dependent upon the IL-4 receptor- chain (IL-4R). IL-13 has been further implicated in the overproduction of mucus by the airway epithelium and in lung remodeling that commonly accompanies chronic inflammation. IL-4R–deficient mice are resistant to allergen-induced asthma, highlighting the therapeutic promise of selective molecular inhibitors of IL-4R. We designed a chemically modified IL-4R antisense oligonucleotide (IL-4R ASO) that specifically inhibits IL-4R protein expression in lung eosinophils, macrophages, dendritic cells, and airway epithelium after inhalation in allergen-challenged mice. Inhalation of IL-4R ASO attenuated allergen-induced AHR, suppressed airway eosinophilia and neutrophilia, and inhibited production of airway Th2 cytokines and chemokines in previously allergen-primed and -challenged mice. Histologic analysis of lungs from these animals demonstrated reduced goblet cell metaplasia and mucus staining that correlated with inhibition of Muc5AC gene expression in lung tissue. Therapeutic administration of inhaled IL-4R ASO in chronically allergen-challenged mice produced a spectrum of anti-inflammatory activity similar to that of systemically administered Dexamethasone with the added benefit of reduced airway neutrophilia. These data support the potential utility of a dual IL-4 and IL-13 oligonucleotide inhibitor in allergy/asthma, and suggest that local inhibition of IL-4R in the lung is sufficient to suppress allergen-induced pulmonary inflammation and AHR.

Key Words: allergy • chronic asthma • antisense oligonucleotide

CLINICAL RELEVANCE IL-4 receptor reduction restricted to the pulmonary compartment is sufficient to suppress lung inflammation and airways hyperresponsiveness in an asthma model. These findings support an inhaled IL-4 receptor antisense oligonucleotide therapeutic strategy for asthma.

 

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