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Nat Commun
. 2022 Aug 3;13(1):4503.
doi: 10.1038/s41467-022-32216-0.
An intranasal ASO therapeutic targeting SARS-CoV-2
Chi Zhu 1 2 , Justin Y Lee 1 2 , Jia Z Woo 3 4 , Lei Xu 1 2 , Xammy Nguyenla 5 , Livia H Yamashiro 6 , Fei Ji 7 , Scott B Biering 5 , Erik Van Dis 6 , Federico Gonzalez 1 2 , Douglas Fox 5 , Eddie Wehri 8 , Arjun Rustagi 9 , Benjamin A Pinsky 9 10 , Julia Schaletzky 8 , Catherine A Blish 9 , Charles Chiu 11 , Eva Harris 5 , Ruslan I Sadreyev 7 , Sarah Stanley 5 6 , Sakari Kauppinen 12 , Silvi Rouskin 3 4 , Anders M Näär 13 14
Affiliations
- PMID: 35922434
- DOI: 10.1038/s41467-022-32216-0
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.