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Published ahead of print on September 21, 2006, doi:10.1165/rcmb.2005-0456OC

Am. J. Respir. Cell Mol. Biol., Volume 36, Number 3, March 2007, 276-285

A more recent version of this article appeared on March 1, 2007
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Submitted on December 12, 2005
Revised on September 19, 2006

Anti-inflammatory Activity of Inhaled Interleukin-4 Receptor-{alpha} Antisense Oligonucleotide in Mice

James G Karras1*, Jeffrey R Crosby2, Mausumee Guha2, David Tung2, Doreen A Miller2, William A Gaarde2, Richard S Geary3, Brett P Monia2, and Susan A Gregory1

1 Department of Clinical Development, Isis Pharmaceuticals, Carlsbad, CA, USA, 2 Department of Antisense Drug Discovery, Isis Pharmaceuticals, Carlsbad, CA, USA, 3 Department of Pharmacokinetics, Isis Pharmaceuticals, Carlsbad, CA, USA

* To whom correspondence should be addressed. E-mail: jkarras{at}isisph.com.

The Th2 cytokines IL-4 and IL-13 mediate allergic pulmonary inflammation and airways hyper-reactivity (AHR) in asthma models through signaling dependent upon the IL-4 receptor-{alpha} chain (IL-4R{alpha}). 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{alpha}-deficient mice are resistant to allergen-induced asthma, highlighting the therapeutic promise of selective molecular inhibitors of IL-4R{alpha}. We designed a chemically modified IL-4R{alpha} antisense oligonucleotide (IL-4R{alpha} ASO) that specifically inhibits IL-4R{alpha} protein expression in lung eosinophils, macrophages, dendritic cells, and airway epithelium following inhalation in allergen challenged mice. Inhalation of IL-4R{alpha} 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. Histological 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{alpha} 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{alpha} in the lung is sufficient to suppress allergen induced pulmonary inflammation and AHR.




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