Therapy of respiratory viral infections with intranasal siRNAs

Abstract

Chemically synthesized short interfering RNA (siRNA) has ushered a new era in the application of RNA interference (RNAi) against viral genes. We have paid particular attention to respiratory viruses that wreak heavy morbidity and mortality worldwide. The clinically signifi cant ones include respiratory syncytial virus (RSV), parainfl uenza virus (PIV) (two Paramyxoviruses), and infl uenza virus (an Orthomyxovirus). As the infection by these viruses is clinically restricted to the respiratory tissues, mainly the lungs, the logical route for the application of the siRNA was also the same, i.e., via the nasal route. Following the initial success of single intranasal siRNA against RSV, we now offer two new strategies: (1) second-generation siRNAs, used against the paramyxoviral RNA polymerase large subunit (L), (2) siRNA cocktail with a novel transfection reagent, used against infl uenza virus. Based on these results, we propose the following consensus for designing intranasal antiviral siRNAs: (a) modifi ed 19–27 nt-long double-stranded siRNAs are functional in the lung, (b) excessive 2′-OMe and 2′-F modifi cations in either or both strands of these siRNAs reduce effi cacy, (c) limited modifi cations in the sense strand are benefi cial, although their precise effi cacy may be position-dependent, (d) cocktail of multiple siRNAs can be highly effective against multiple viral strains and subtypes.