Therapy for drug resistant influenza strains by nucleic acid targeting of respiratory airways

PROJECT SUMMARY Antiviral drugs are a crucial countermeasure for influenza A virus IAV particularly in circumstances of increased IAV incidence or if a vaccine is unavailable e g virulent H N IAV However the emergence of IAV strains that are resistant to current antivirals H N underscores the need for new treatment strategies particularly those that modify the host response IAVs infect of the US population with andgt hospitalizations and deaths annually Morbidity and mortality are secondary to an intense systemic stress to the antiviral immune response particularly in those individuals with co morbidities i e chronic respiratory and cardiovascular diseases Additionally endemic IAV strains from other species e g H N can kill healthy individuals by a cytokine storm The emergence of pandemic strains is inevitable as seen most recently with H N Moreover IAV s ability to rapidly acquire increased virulence and efficient human to human transmission through genetic shift is a constant threat to the global population and benign strains may rapidly evolve and cause severe morbidity and mortality This application proposes to develop for use in patients a novel therapeutic gene knockdown strategy localized to respiratory epithelium by employing nanoplexes an electrostatic complex of cationic polymers and anionic nucleic acids Our preliminary findings have demonstrated that this antiviral therapy inhibits IAV replication decreases IAV induced lung injury and improves antibacterial host responses This Phase I STTR application will optimize the fabrication and delivery of the nanoplexes and establish its in vitro efficacy with respect to antiviral and IFN I stimulating activity and toxicity The subsequent Phase II STTR application will determine its in vivo efficacy and toxicity in mice and ferrets utilizing drug resistant laboratory epidemic pandemic and pathogenic strains PROJECT NARRATIVE The proposed STTR Phase I project will test the effectiveness of RNA delivery for therapeutic applications in influenza treatment Success will be the basis for a Phase II application dedicated to expanded assessment and scaled production of a potential new therapy for influenza