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Published ahead of print on January 31, 2008, doi:10.1164/rccm.200708-1251OC

Am. J. Respir. Crit. Care Med., Volume 177, Number 9, May 2008, 952-958

A more recent version of this article appeared on May 1, 2008
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Submitted on August 23, 2007
Accepted on January 31, 2008

Antisense Therapy Against CCR3 and the Common Beta Chain Attenuates Allergen-Induced Responses

Gail M Gauvreau1*, Louis Philippe Boulet2, Donald W Cockcroft3, Adrian Baatjes1, Johanne Cote2, Francine Deschesnes2, Beth Davis3, Tara Strinich1, Karen Howie1, MyLinh Duong1, Richard M Watson1, Paolo M Renzi4, and Paul M O'Byrne1

1 Department of Medicine, McMaster University, Hamilton, ON, Canada, 2 Institut de cardiologie et de pneumologie de l'Universite Laval, Hopital Laval, Quebec City, QC, Canada, 3 Division of Respiratory Medicine, University of Saskatchewan, Saskatoon, SK, Canada, 4 University of Montreal andTopigen Pharmaceuticals, Montreal, QC, Canada

* To whom correspondence should be addressed. E-mail: gauvreau{at}mcmaster.ca.

Rationalse: TPI ASM8 contains two modified phosphorothioate antisense oligonucleotides, designed to inhibit allergic inflammation by down-regulating human CCR3 and the common beta chain ({beta}c) of IL-3, IL-5, and GM-CSF receptors. This study examined the effects of inhaled TPI ASM8 on sputum cellular influx, CCR3 and {beta}c mRNA and protein levels and the airway physiological response after inhaled allergen. Methods: Seventeen subjects with mild atopic asthma were randomized in a crossover study to inhale 1500 mcg TPI ASM8 or placebo by nebulizer, once daily for 4 days. On Day 3, subjects underwent allergen inhalation challenge. Sputum samples were collected before and after allergen. CCR3 and {beta}c protein levels were measured by flow cytometry, mRNA was measured using real time quantitative PCR and the FEV1 was measured over 7 hours after challenge. Results: Compared to placebo, TPI ASM8 inhibited sputum eosinophil influx by 46 % (p=0.02) and blunted the increase in total cells (63%) after allergen challenge. TPI ASM8 significantly reduced the EAR (p= 0.03) with a trend for the LAR (p= 0.08). The allergen-induced (Day 2 to Day 3) levels of {beta}c mRNA and CCR3 mRNA in sputum-derived cells was inhibited by TPI ASM8 (p=0.039 and p=0.055, respectively) with no significant effects on the cell surface protein expression of CCR3 and {beta}c (p>0.05). No serious adverse events were reported. Conclusions: TPI ASM8 attenuates the allergen-induced increase in target gene mRNA and airway responses in subjects with mild asthma. Clinical Trials Registry Information: ID# NCT00264966 registered at www.clinicaltrials.gov
Key words: antisense oligonucleotides, eosinophils, allergen inhalation, airway inflammation






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