An intranasal ASO therapeutic targeting SARS-CoV-2

An intranasal ASO therapeutic targeting SARS-CoV-2

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...

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Main Authors: Chi Zhu, Justin Y. Lee, Jia Z. Woo, Lei Xu, Xammy Huu Wrynla, Livia H. Yamashiro, Fei Ji, Scott B. Biering, Erik Van 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, Anders M. Näär
Format: Article
Language:English
Published: Nature Portfolio 2022-08-01
Series:Nature Communications
Online Access:https://doi.org/10.1038/s41467-022-32216-0
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Summary: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.
ISSN:2041-1723

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