Suppression of Il5 and Il13 Gene Expression by Synthetic siRNA Molecules Reduces Nasal Hyperreactivity and Inflammation in a Murine Model of Allergic Rhinitis

Abstract

Th2 cytokines (IL-4, IL-5, and IL-13) play an important role in the development of allergies, including allergic rhinitis (AR). IL-13 promotes mucus hyperproduction in the airway and IL-5 recruits eosinophils to the nasal mucosa, leading to increased inflammation and tissue damage. Drugs based on monoclonal antibodies that block the activity of these cytokines are being developed for the treatment of allergic diseases. However, studies of drugs that target IL-13 alone (such as Tralokinumab and Lebrikizumab) were not successful. Given that IL-5 and IL-13 have different roles in AR, simultaneous inhibition of both cytokines may be a promising approach. New methods of regulating gene activity, such as RNA interference (RNAi), offer new perspectives for the development of drugs. This study describes a complex consisting of siRNA that inhibit the activity of Il5 and Il13 genes and a currier peptide LTP (cationic dendrimeric peptide). The effects of this complex on the allergic inflammation in the murine AR model was studied. Suppression of Il5 expression decreased nasal hyperreactivity and reduced the number of goblet cells in the respiratory epithelium of AR-induced mice. Inhibiting the Il13 gene had a more beneficial effect than suppression Il5 alone, further contributing to reducing the number of cells infiltration the nasal cavity. When both Il5 and Il13 were suppressed simultaneously, the result was similar that of Il13 inhibition alone. Likely, IL-13 plays a more significant role in the development of allergic rhinitis than IL-5. As a result, the possibility of using RNAi for anti-cytokine therapy for AR has been demonstrated. However, dual inactivation of IL-5 and IL-13 by siRNA does not provide any advantages over inactivating IL-13 alone in the current mouse model of AR. However, the lack of success of anti-IL-13 therapy in clinical practice indicates the promise of an approach based on the dual blocking of IL-5 and IL-13.