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a CHUM Research Center, Notre-Dame Hospital, Montreal, Quebec, Canada H2L 4M1 b Topigen Pharmaceuticals Inc., Montreal, Quebec, Canada H1W 4A4
Key Words: asthma • common beta chain • CCR3 • airway inflammation • airway hyperresponsiveness
Address for correspondence: Dr. Paolo Renzi, CHUM Research Center, Notre-Dame Hospital, 2065 Alexandre de Sève, Room Z-8905, Montreal, Quebec, Canada, H2L 2W5. Voice: 514-890-8000; ext.: 28031; fax: 514-412-7579. e-mail: renzip{at}earthlink.net
Asthma is characterized by inflammation and hyperresponsiveness related to the accumulation of inflammatory cells, particularly eosinophils, within the airways. We tested the hypothesis that a multitargeted approach is better than a single-targeted approach in a rat model of asthma. We simultaneously delivered oligonucleotides (ODNs) targeting the chemokine receptor CCR3 and the common beta chain subunit of the receptors for IL-3, IL-5, and GM-CSF at the time of ovalbumin challenge in sensitized Brown Norway rats. Fewer eosinophils were detected in bronchoalveolar lavage (BAL) of rats treated with both ODNs as compared to each ODN alone. Moreover, airway responsiveness to LTD4 was significantly decreased at lower doses in the 2 ODN-treated groups compared to a single ODN. As ODN therapy has raised concerns of toxicity we therefore examined ODNs prepared with modified DNA bases, specifically 2'amino, 2'deoxyadenosine (DAP) in place of adenosine. In vivo, administration of individual DAP-ODN was efficacious in inhibiting airway hyperresponsiveness, whereas delivery of 2 DAP-ODNs (targeting CCR3 and common beta chain) reduced the influx not only of eosinophils but also lymphocytes and macrophages in the lungs of rats as compared to the unmodified ODNs. Blocking multiple inflammatory pathways simultaneously is more effective in preventing eosinophilia and airway hyperresponsiveness than inhibiting either pathway alone. The challenges associated with the development of a product containing two oligonucleotides in humans are discussed.
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