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

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).

• Authors: Gail M Gauvreau, Louis Philippe Boulet, Donald W Cockcroft, Adrian Baatjes, Johanne Cote, Francine Deschesnes, Beth Davis, Tara Strinich, Karen Howie, Mylinh Duong, Richard M Watson, Paolo M Renzi, Paul M O'Byrne
• Journal: American journal of respiratory and critical care medicine (Am J Respir Crit Care Med) Vol. 177 Issue 9 Pg. 952-8 (May 01 2008) ISSN: 1535-4970 [Electronic] United States
• PMID: 18244953 (Publication Type: Comparative Study, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Allergens
• CCR3 protein, human
• Drug Combinations
• Oligonucleotides, Antisense
• Phosphorothioate Oligonucleotides
• RNA, Messenger
• Receptors, CCR3
• Receptors, Cytokine
• TPI ASM8
• beta C receptor

Topics

• Administration, Inhalation
• Adult
• Allergens (adverse effects)
• Asthma (drug therapy, genetics, 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, therapeutic use)
• Phosphorothioate Oligonucleotides (administration & dosage, therapeutic use)
• Pulmonary Eosinophilia (drug therapy, genetics, metabolism)
• RNA, Messenger (genetics)
• Receptors, CCR3 (antagonists & inhibitors, genetics, metabolism)
• Receptors, Cytokine (genetics, metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• Sputum (cytology, metabolism)
• Treatment Outcome