1. Antisense therapy against CCR3 and the common beta chain attenuates allergen-induced eosinophilic responses.
- Author
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Gauvreau GM, Boulet LP, Cockcroft DW, Baatjes A, Cote J, Deschesnes F, Davis B, Strinich T, Howie K, Duong M, Watson RM, Renzi PM, and O'Byrne PM
- Subjects
- Administration, Inhalation, Adult, Asthma genetics, Asthma metabolism, Cross-Over Studies, Double-Blind Method, Drug Combinations, Female, Flow Cytometry, Follow-Up Studies, Forced Expiratory Volume, Gene Expression, Humans, Male, Middle Aged, Nebulizers and Vaporizers, Oligonucleotides, Antisense administration & dosage, Phosphorothioate Oligonucleotides administration & dosage, Pulmonary Eosinophilia genetics, Pulmonary Eosinophilia metabolism, RNA, Messenger genetics, Receptors, CCR3 genetics, Receptors, CCR3 metabolism, Receptors, Cytokine genetics, Reverse Transcriptase Polymerase Chain Reaction, Sputum cytology, Sputum metabolism, Treatment Outcome, Allergens adverse effects, Asthma drug therapy, Oligonucleotides, Antisense therapeutic use, Phosphorothioate Oligonucleotides therapeutic use, Pulmonary Eosinophilia drug therapy, Receptors, CCR3 antagonists & inhibitors, Receptors, Cytokine metabolism
- Abstract
Rationale: The drug product 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 granulocyte-macrophage colony-stimulating factor receptors., Objectives: This study examined the effects of inhaled TPI ASM8 on sputum cellular influx, CCR3 and beta(c) mRNA and protein levels, and the airway physiologic response after inhaled allergen., Methods: Seventeen subjects with mild atopic asthma were randomized in a crossover study to inhale 1,500 microg 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 polymerase chain reaction, and the FEV1 was measured over 7 hours after challenge., Measurements and Main Results: Compared with 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 early asthmatic response (P = 0.04) with a trend for the late asthmatic response (P = 0.08). The allergen-induced (Day 2 to Day 3) levels of beta(c) mRNA and CCR3 mRNA in sputum-derived cells were inhibited by TPI ASM8 (P = 0.039 and P = 0.054, 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 trial registered with www.clinicaltrials.gov (NCT 00264966).
- Published
- 2008
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