title: Anti-inflammatory activity of inhaled IL-4 receptor-alpha antisense oligonucleotide in mice.
abstract: 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-alpha chain (IL-4Ralpha). 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-4Ralpha-deficient mice are resistant to allergen-induced asthma, highlighting the therapeutic promise of selective molecular inhibitors of IL-4Ralpha. We designed a chemically modified IL-4Ralpha antisense oligonucleotide (IL-4Ralpha ASO) that specifically inhibits IL-4Ralpha protein expression in lung eosinophils, macrophages, dendritic cells, and airway epithelium after inhalation in allergen-challenged mice. Inhalation of IL-4Ralpha 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-4Ralpha 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-4Ralpha in the lung is sufficient to suppress allergen-induced pulmonary inflammation and AHR.
authors.affiliation: Department of Clinical Development, Pharmaceuticals, 1896 Rutherford Road, Carlsbad, CA 92008, USA. jkarras@isisph.com
authors.forename: James G
authors.initials: JG
authors.lastname: Karras
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Crosby
authors.forename: Mausumee
authors.initials: M
authors.lastname: Guha
authors.forename: David
authors.initials: D
authors.lastname: Tung
authors.forename: Doreen A
authors.initials: DA
authors.lastname: Miller
authors.forename: William A
authors.initials: WA
authors.lastname: Gaarde
authors.forename: Richard S
authors.initials: RS
authors.lastname: Geary
authors.forename: Brett P
authors.initials: BP
authors.lastname: Monia
authors.forename: Susan A
authors.initials: SA
authors.lastname: Gregory
mesh_terms: D000280:Administration, Inhalation; D000336:Aerosols; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000378:metabolism*; D001249:Asthma / Q000503:physiopathology; D016535:Bronchial Hyperreactivity / Q000628:therapy; D001985:Bronchial Provocation Tests; D018925:Chemokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D004804:Eosinophils / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D020397:Goblet Cells / Q000187:drug effects / Q000473:pathology; D007249:Inflammation; D008168:Lung / Q000187:drug effects / Q000473:pathology; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008679:Metaplasia; D051379:Mice; D009077:Mucins / Q000235:genetics / Q000378:metabolism; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage / Q000494:pharmacology*; D010047:Ovalbumin; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology; D016896:Treatment Outcome; D053662:Interleukin-4 Receptor alpha Subunit
chemical_list: D000336:Aerosols; D000893:Anti-Inflammatory Agents; D018925:Chemokines; D009077:Mucins; D016376:Oligonucleotides, Antisense; D010047:Ovalbumin; D011956:Receptors, Cell Surface; C504002:Il4ra protein, mouse; D053662:Interleukin-4 Receptor alpha Subunit