Delivery of RNAi Therapeutics to the Airways—From Bench to Bedside

Qiu, Yingshan; Lam, Jenny K. W.; Leung, Susan W. S.; Liang, Wanling

Targeting suppressor of cytokine signaling (SOCS) 3 is an alternative approach [12] . SOCS proteins are negative regulators of cytokine signaling pathway, which are involved in T h 2 cells mediated allergic response via controlling the balance between T h 2 and T h 1 cells [189] . The expression of SOCS3 is a pathological marker of allergic disease. After siRNA targeting, SOCS3 was intranasally administered to the lungs of chronic asthmatic mouse model [12] , the silencing of SOCS3 down-regulated the expression of T h 2 cell associated cytokines, IL-4, IL-5 and IL-13, leading to substantial reduction of airway inflammation, AHR as well as IgE production. Reduction of mucus secretion and collagen deposition was also detected in the airways. Besides T h 2 cell, other T cells subsets, such as T h 9 and T h 17 cells, also contribute the inflammatory response in asthma by releasing IL-9 and IL-17A. These molecules may also be the potential targets for RNAi therapy [183] . Furthermore, the combination of inflammatory and antiviral siRNAs is a prospective therapy for patients with virus-induced exacerbation of severe uncontrolled asthma, in view of the report that respiratory viral infection is related to 80% of asthma exacerbation in children and adults [190] . The therapeutic potential of targeting IL-4 and P protein of RSV simultaneously by siRNAs was examined in a mouse model of RSV-induced asthma exacerbation [181] . The intranasal delivery of the two siRNAs was able to: (i) significantly suppress IL-4 mRNA expression and RSV replication in the lungs; (ii) reduce eosinophil and neutrophil infiltration in bronchoalveolar lavage fluid (BALF); (iii) inhibit AHR and inflammation; and (iv) increase interferon (IFN)-γ expression.