An intranasal ASO therapeutic targeting SARS-CoV-2

Chi Zhu, Justin Y. Lee, Jia Z. Woo, Lei Xu, Xammy Nguyenla, Livia H. Yamashiro, Fei Ji, Scott B. Biering, Erik Dis, Federico Gonzalez, Douglas Fox, Eddie Wehri, Arjun Rustagi, Benjamin A. Pinsky, Julia Schaletzky, Catherine A. Blish, Charles Chiu, Eva Harris, Ruslan I. Sadreyev, Sarah Stanley, Sakari Kauppinen, Silvi Rouskin and Anders M. Näär ()
Additional contact information
Chi Zhu: University of California
Justin Y. Lee: University of California
Jia Z. Woo: Whitehead Institute for Biomedical Research
Lei Xu: University of California
Xammy Nguyenla: University of California, Berkeley
Livia H. Yamashiro: University of California
Fei Ji: Massachusetts General Hospital
Scott B. Biering: University of California, Berkeley
Erik Dis: University of California
Federico Gonzalez: University of California
Douglas Fox: University of California, Berkeley
Eddie Wehri: University of California
Arjun Rustagi: Stanford University, School of Medicine
Benjamin A. Pinsky: Stanford University, School of Medicine
Julia Schaletzky: University of California
Catherine A. Blish: Stanford University, School of Medicine
Charles Chiu: University of California
Eva Harris: University of California, Berkeley
Ruslan I. Sadreyev: Massachusetts General Hospital
Sarah Stanley: University of California, Berkeley
Sakari Kauppinen: Aalborg University
Silvi Rouskin: Whitehead Institute for Biomedical Research
Anders M. Näär: University of California

Nature Communications, 2022, vol. 13, issue 1, 1-13

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-32216-0

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