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

• Published in: American journal of respiratory and critical care medicine Vol. 177; no. 9; pp. 952 - 958
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: New York, NY Am Thoracic Soc 01.05.2008; American Lung Association; American Thoracic Society
• Subjects: Administration, Inhalation; Adult; Allergens - adverse effects; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Asthma - drug therapy; Asthma - genetics; Asthma - metabolism; Biological and medical sciences; Cross-Over Studies; Double-Blind Method; Drug Combinations; Female; Flow Cytometry; Follow-Up Studies; Forced Expiratory Volume; Gene Expression; Humans; Intensive care medicine; Male; Medical sciences; Middle Aged; Nebulizers and Vaporizers; Oligonucleotides, Antisense - administration & dosage; Oligonucleotides, Antisense - therapeutic use; Pharmacology. Drug treatments; Phosphorothioate Oligonucleotides - administration & dosage; Phosphorothioate Oligonucleotides - therapeutic use; Pulmonary Eosinophilia - drug therapy; Pulmonary Eosinophilia - genetics; Pulmonary Eosinophilia - metabolism; Receptors, CCR3 - antagonists & inhibitors; Receptors, CCR3 - genetics; Receptors, CCR3 - metabolism; Receptors, Cytokine - genetics; Receptors, Cytokine - metabolism; Respiratory system; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; Sputum - cytology; Sputum - metabolism; Treatment Outcome; airway inflammation; Immunopathology; Allergy; Intensive care; eosinophils; Inflammation; Chemokine receptor; Eosinophil; Inhalation; allergen inhalation; Treatment; antisense oligonucleotides; Resuscitation
• ISSN: 1073-449X; 1535-4970; 1535-4970
• DOI: 10.1164/rccm.200708-1251OC

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) (P > 0.05). 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).