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An intranasal ASO therapeutic targeting SARS-CoV-2

Author

Listed:
  • Chi Zhu

    (University of California
    University of California)

  • Justin Y. Lee

    (University of California
    University of California)

  • Jia Z. Woo

    (Whitehead Institute for Biomedical Research
    Harvard Medical School)

  • Lei Xu

    (University of California
    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
    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
    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
    University of California)

  • Sakari Kauppinen

    (Aalborg University)

  • Silvi Rouskin

    (Whitehead Institute for Biomedical Research
    Harvard Medical School)

  • Anders M. Näär

    (University of California
    University of California)

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.

Suggested Citation

  • 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., 2022. "An intranasal ASO therapeutic targeting SARS-CoV-2," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-32216-0
    DOI: 10.1038/s41467-022-32216-0
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    as
    1. Nicholas G. Davies & Christopher I. Jarvis & W. John Edmunds & Nicholas P. Jewell & Karla Diaz-Ordaz & Ruth H. Keogh, 2021. "Increased mortality in community-tested cases of SARS-CoV-2 lineage B.1.1.7," Nature, Nature, vol. 593(7858), pages 270-274, May.
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