Effect of chemically modified IL-13 short interfering RNA on development of airway hyperresponsiveness in mice

Background

RNA interference is an endogenous cellular mechanism in which short interfering RNAs (siRNAs) direct the sequence specific degradation of a target mRNA. siRNAs can be synthesized with chemical modifications to increase stability and reduce double-stranded RNA–induced immune responses without affecting their ability to elicit degradation of target mRNA.

Objectives

This study examined the use of chemically modified siRNAs in a mouse model of allergen-induced airway hyperresponsiveness.

Methods

Chemically modified siRNAs were designed and screened in a cell-based reporter assay. The most potent siRNAs were then screened in bone marrow–derived mast cells to demonstrate efficacy in primary cells.

Results

A candidate siRNA was formulated and administered to sensitized mice just before airway challenge with allergen. Administration of the siRNA was shown to reduce airway resistance significantly in sensitized and challenged mice by 60%, whereas a control siRNA had no effect.

Conclusion

These data demonstrate the effectiveness of introducing targeted siRNAs to prevent induction of allergen-induced airway dysfunction and suggest potential therapeutic applications.

Key words: siRNA, IL-13, AHR, eosinophilia

Abbreviations used: AHR, Airway hyperresponsiveness, BAL, Bronchoalveolar lavage, BMMC, Bone marrow–derived mast cell, dsRNA, Double-stranded RNA, GFP, Green fluorescence protein, HE, Hematoxylin-eosin, MCh, Methacholine, OVA, Ovalbumin, PAS, Periodic acid-Schiff, RL, Lung resistance, siRNA, Short interfering RNA