Antisense therapy against CCR3 and the common beta chain attenuates allergen-induced eosinophilic responses

作者：Gauvreau Gail M^*; Boulet Louis Philippe; Cockcroft Donald W; Baatjes Adrian; Cote Johanne; Deschesnes Francine; Davis Beth; Strinich Tara; Howie Karen; Duong MyLinh; Watson Richard M; Renzi Paolo M; O'Byrne Paul M

来源：American Journal of Respiratory and Critical Care Medicine, 2008, 177(9): 952-958.

DOI：10.1164/rccm.200708-1251

• antisense oligonucleotides
• eosinophils
• allergen inhalation
• airway inflammation

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 mu g 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 Pc 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).

• 出版日期2008-5-1