Local administration of antisense phosphorothioate oligonucleotides to thec-kit ligand, stem cell factor, suppresses airway inflammation and IL-4 production in a murine model of asthma

Background: The c-kit ligand, stem cell factor (SCF), is an important activ ating and chemotactic factor for both mast cells and eosinophils, These cel ls are known to play a fundamental role in the pathogenesis of asthma. Objective: Our goal was to analyze the functional role of SCF in the pathog enesis of asthma. Methods: The expression of SCF was targeted in fibroblasts, epithelial cell s, and locally in a murine model of asthma in mice induced by ovalbumin sen sitization with an antisense DNA strategy. Results: We could suppress SCF expression in NIH 3T3 fibroblasts and SP1 ep ithelial cells by a specific antisense phosphorothioate oligonucleotide ove rlapping the translation start site of SCF, whereas control oligonucleotide s were virtually inactive. We then focused on the role of SCF in a murine m odel of asthma associated with late-phase allergic inflammation in ovalbumi n-sensitized mice: Local intranasal administration of FITC-labeled SCF anti sense oligonucleotides led to strong DNA uptake in interstitial lung cells associated with a striking reduction of intracellular SCF expression. Such intrapulmonary blockade of SCF expression after repeated allergen challenge s suppressed various signs of lung inflammation including IL-4 production a nd infiltration of eosinophils. SCF antisense DNA treatment was at least as effective as corticosteroid treatment. Conclusion: These data indicate a critical role for SCP in a murine asthma model and suggest that local delivery of SCF antisense oligonucleotides may be a novel approach for the treatment of inflammatory lung disorders such as asthma.