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.
Original language | English |
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Article number | 4503 |
Journal | Nature Communications |
Volume | 13 |
Issue number | 1 |
Pages (from-to) | 4503 |
ISSN | 2041-1723 |
DOIs | |
Publication status | Published - 3 Aug 2022 |
Bibliographical note
© 2022. The Author(s).Keywords
- Administration, Intranasal
- Animals
- COVID-19
- Humans
- Mice
- Oligonucleotides, Antisense/pharmacology
- Pandemics/prevention & control
- RNA, Viral/genetics
- SARS-CoV-2