Abstract
The COVID-19 pandemic is exacting an increasing toll worldwide, with new SARS-CoV-2 variants emerging that exhibit higher infectivity rates and that may partially evade vaccine and antibody immunity. Rapid deployment of non-invasive therapeutic avenues capable of preventing infection by all SARS-CoV-2 variants could complement current vaccination efforts and help turn the tide on the COVID-19 pandemic. Here, we describe a novel therapeutic strategy targeting the SARS-CoV-2 RNA using locked nucleic acid antisense oligonucleotides (LNA ASOs). We identify an LNA ASO binding to the 5′ leader sequence of SARS-CoV-2 that disrupts a highly conserved stem-loop structure with nanomolar efficacy in preventing viral replication in human cells. Daily intranasal administration of this LNA ASO in the COVID-19 mouse model potently suppresses viral replication (>80-fold) in the lungs of infected mice. We find that the LNA ASO is efficacious in countering all SARS-CoV-2 “variants of concern” tested both in vitro and in vivo. Hence, inhaled LNA ASOs targeting SARS-CoV-2 represents a promising therapeutic approach to reduce or prevent transmission and decrease severity of COVID-19 in infected individuals. LNA ASOs are chemically stable and can be flexibly modified to target different viral RNA sequences and could be stockpiled for future coronavirus pandemics.
【초록키워드】 COVID-19, SARS-CoV-2, Efficacy, Vaccine, coronavirus, vaccination, COVID-19 pandemic, variant, SARS-CoV-2 variant, lung, Transmission, complement, in vitro, RNA, nucleic acid, Viral, mice, severity of COVID-19, viral replication, Lungs, therapeutic, Pandemics, Rapid, Inhaled, leader sequence, SARS-CoV-2 RNA, Viral RNA, in vivo, therapeutic strategy, intranasal, binding, administration, Antisense oligonucleotide, Therapeutic approach, Non-invasive, infected individuals, sequence, human cells, help, effort, antibody immunity, higher infectivity, tide, Daily, Prevent, ASO, decrease, new SARS-CoV-2, tested, identify, conserved, evade, suppresse, reduce, turn, disrupt, preventing infection, the SARS-CoV-2, 【제목키워드】 SARS-CoV-2, intranasal, therapeutic targeting, ASO,