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An intranasal ASO therapeutic targeting SARS-CoV-2
- Zhu, Chi;
- Lee, Justin Y;
- Woo, Jia Z;
- Xu, Lei;
- Nguyenla, Xammy;
- Yamashiro, Livia H;
- Ji, Fei;
- Biering, Scott B;
- Van Dis, Erik;
- Gonzalez, Federico;
- Fox, Douglas;
- Wehri, Eddie;
- Rustagi, Arjun;
- Pinsky, Benjamin A;
- Schaletzky, Julia;
- Blish, Catherine A;
- Chiu, Charles;
- Harris, Eva;
- Sadreyev, Ruslan I;
- Stanley, Sarah;
- Kauppinen, Sakari;
- Rouskin, Silvi;
- Näär, Anders M
- et al.
Published Web Location
https://doi.org/10.1038/s41467-022-32216-0Abstract
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.
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