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Antisense therapy against CCR3 and the common beta chain attenuates allergen-induced eosinophilic responses.
- Source :
-
American journal of respiratory and critical care medicine [Am J Respir Crit Care Med] 2008 May 01; Vol. 177 (9), pp. 952-8. Date of Electronic Publication: 2008 Jan 31. - Publication Year :
- 2008
-
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.<br />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.<br />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.<br />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.<br />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).
- 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
Subjects
Details
- Language :
- English
- ISSN :
- 1535-4970
- Volume :
- 177
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- American journal of respiratory and critical care medicine
- Publication Type :
- Academic Journal
- Accession number :
- 18244953
- Full Text :
- https://doi.org/10.1164/rccm.200708-1251OC