title: 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 significant ones include respiratory syncytial virus (RSV), parainfluenza virus (PIV) (two Paramyxoviruses), and influenza 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 influenza virus. Based on these results, we propose the following consensus for designing intranasal antiviral siRNAs: (a) modified 19-27 nt-long double-stranded siRNAs are functional in the lung, (b) excessive 2'-OMe and 2'-F modifications in either or both strands of these siRNAs reduce efficacy, (c) limited modifications in the sense strand are beneficial, although their precise efficacy may be position-dependent, (d) cocktail of multiple siRNAs can be highly effective against multiple viral strains and subtypes.
authors.affiliation: Center for Gene Regulation in Health and Disease, Cleveland State University, Cleveland, OH, USA, s.barik@csuohio.edu.
authors.forename: Sailen
authors.initials: S
authors.lastname: Barik
authors.forename: Patrick
authors.initials: P
authors.lastname: Lu
mesh_terms: D000281:Administration, Intranasal; D000818:Animals; D002460:Cell Line; D012321:DNA-Directed RNA Polymerases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism / Q000821:virology; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D019590:Nucleocapsid Proteins; D009975:Orthomyxoviridae / Q000235:genetics; D009976:Orthomyxoviridae Infections / Q000235:genetics / Q000628:therapy* / Q000821:virology; D018184:Paramyxoviridae Infections / Q000235:genetics / Q000628:therapy* / Q000821:virology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D018108:Respirovirus / Q000235:genetics; D013329:Structure-Activity Relationship; D014758:Viral Core Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D014763:Viral Matrix Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D014764:Viral Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000086082:Viroporin Proteins
chemical_list: D012321:DNA-Directed RNA Polymerases; D019590:Nucleocapsid Proteins; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; D014758:Viral Core Proteins; D014763:Viral Matrix Proteins; D014764:Viral Proteins; C488937:M2 protein, Influenza A virus; D000086082:Viroporin Proteins; C048842:NP protein, Influenza A virus