Antisense Therapy against CCR3 and the Common Beta Chain Attenuates Allergen-induced Eosinophilic Responses

Autor: Karen Howie, Louis-Philippe Boulet, Adrian J Baatjes, Tara X. Strinich, Donald W. Cockcroft, MyLinh Duong, Beth E. Davis, Richard M. Watson, Paul M. O'Byrne, Paolo M. Renzi, Francine Deschesnes, Gail M. Gauvreau, Johanne Côté
Rok vydání: 2008
Předmět:
Adult
Male
Pulmonary and Respiratory Medicine
Allergy
Receptors
CCR3
government.form_of_government
Gene Expression
Phosphorothioate Oligonucleotides
Critical Care and Intensive Care Medicine
medicine.disease_cause
Allergic inflammation
Allergen
Double-Blind Method
immune system diseases
Forced Expiratory Volume
Intensive care
Administration
Inhalation
Humans
Medicine
RNA
Messenger
Pulmonary Eosinophilia
Receptors
Cytokine
Antisense therapy
Cross-Over Studies
Reverse Transcriptase Polymerase Chain Reaction
business.industry
Nebulizers and Vaporizers
Sputum
Allergens
Middle Aged
Oligonucleotides
Antisense
Eosinophil
Flow Cytometry
medicine.disease
Asthma
respiratory tract diseases
Drug Combinations
Treatment Outcome
Real-time polymerase chain reaction
medicine.anatomical_structure
Immunology
government
Female
medicine.symptom
business
Follow-Up Studies
Zdroj: American Journal of Respiratory and Critical Care Medicine. 177:952-958
ISSN: 1535-4970
1073-449X
DOI: 10.1164/rccm.200708-1251oc
Popis: 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.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.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.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) (P0.05). No serious adverse events were reported.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).
Databáze: OpenAIRE
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