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