Acute respiratory infections are a major global health burden. Seasonal influenza alone causes 290,000 to 650,000 respiratory deaths annually. Novel IAV variants produced by reassortment events in IAV constantly presents a threat of pandemic outbreak. Current therapeutic drugs that target critical influenza proteins are reported to be susceptible to escape mutations in the circulating seasonal strains. An influenza outbreak adds to the selective pressure leading to an accelerated drug resistance.
In this study, we designed influenza segment-specific gapmer anti-sense oligonucleotides (ASO) across all 8 segments of prevalent strains. Through a screen of 63 ASOs, we validated several ASOs that showed viral repression in both H3N2 and H1N1 viruses. These ASOs were also observed to have low IC50 concentration and maintained cell viability. Our work presents a proof-of-concept that ASOs can be designed to target multiple circulating strains or designed against novel strains and remain effective with mismatches to hedge against escape mutations.