IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v13y2022i1d10.1038_s41467-022-32216-0.html
   My bibliography  Save this article

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
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-022-32216-0
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-022-32216-0?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    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.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Sheng-Chieh Lee & Ching-Yuan Lin & Ying-Ji Chuang, 2022. "The Study of Alternative Fire Commanders’ Training Program during the COVID-19 Pandemic Situation in New Taipei City, Taiwan," IJERPH, MDPI, vol. 19(11), pages 1-22, May.
    2. Juan Yang & Valentina Marziano & Xiaowei Deng & Giorgio Guzzetta & Juanjuan Zhang & Filippo Trentini & Jun Cai & Piero Poletti & Wen Zheng & Wei Wang & Qianhui Wu & Zeyao Zhao & Kaige Dong & Guangjie , 2021. "Despite vaccination, China needs non-pharmaceutical interventions to prevent widespread outbreaks of COVID-19 in 2021," Nature Human Behaviour, Nature, vol. 5(8), pages 1009-1020, August.
    3. Rosanna C. Barnard & Nicholas G. Davies & Mark Jit & W. John Edmunds, 2022. "Modelling the medium-term dynamics of SARS-CoV-2 transmission in England in the Omicron era," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    4. Mitze, Timo & Rode, Johannes, 2022. "Early-stage spatial disease surveillance of novel SARS-CoV-2 variants of concern in Germany with crowdsourced data," Publications of Darmstadt Technical University, Institute for Business Studies (BWL) 130543, Darmstadt Technical University, Department of Business Administration, Economics and Law, Institute for Business Studies (BWL).
    5. Lei Peng & Yingxia Hu & Madeleine C. Mankowski & Ping Ren & Rita E. Chen & Jin Wei & Min Zhao & Tongqing Li & Therese Tripler & Lupeng Ye & Ryan D. Chow & Zhenhao Fang & Chunxiang Wu & Matthew B. Dong, 2022. "Monospecific and bispecific monoclonal SARS-CoV-2 neutralizing antibodies that maintain potency against B.1.617," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    6. Mario Coccia, 2023. "COVID-19 Vaccination is not a Sufficient Public Policy to face Crisis Management of next Pandemic Threats," Public Organization Review, Springer, vol. 23(4), pages 1353-1367, December.
    7. So Kubota, 2021. "The macroeconomics of COVID-19 exit strategy: the case of Japan," The Japanese Economic Review, Springer, vol. 72(4), pages 651-682, October.
    8. Beatrice Casati & Joseph Peter Verdi & Alexander Hempelmann & Maximilian Kittel & Andrea Gutierrez Klaebisch & Bianca Meister & Sybille Welker & Sonal Asthana & Salvatore Giorgio & Pavle Boskovic & Ka, 2022. "Rapid, adaptable and sensitive Cas13-based COVID-19 diagnostics using ADESSO," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    9. Chengzhuo Tong & Wenzhong Shi & Anshu Zhang & Zhicheng Shi, 2023. "Predicting onset risk of COVID-19 symptom to support healthy travel route planning in the new normal of long-term coexistence with SARS-CoV-2," Environment and Planning B, , vol. 50(5), pages 1212-1227, June.
    10. Wenjuan Dong & Jing Wang & Lei Tian & Jianying Zhang & Erik W. Settles & Chao Qin & Daniel R. Steinken-Kollath & Ashley N. Itogawa & Kimberly R. Celona & Jinhee Yi & Mitchell Bryant & Heather Mead & S, 2023. "Factor Xa cleaves SARS-CoV-2 spike protein to block viral entry and infection," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    11. Shirley Gee Hoon Tang & Muhamad Haziq Hasnul Hadi & Siti Rosilah Arsad & Pin Jern Ker & Santhi Ramanathan & Nayli Aliah Mohd Afandi & Madihah Mohd Afzal & Mei Wyin Yaw & Prajindra Sankar Krishnan & Ch, 2022. "Prerequisite for COVID-19 Prediction: A Review on Factors Affecting the Infection Rate," IJERPH, MDPI, vol. 19(20), pages 1-38, October.
    12. Antoni G. Wrobel & Donald J. Benton & Chloë Roustan & Annabel Borg & Saira Hussain & Stephen R. Martin & Peter B. Rosenthal & John J. Skehel & Steven J. Gamblin, 2022. "Evolution of the SARS-CoV-2 spike protein in the human host," Nature Communications, Nature, vol. 13(1), pages 1-7, December.
    13. Elham Khatamzas & Markus H. Antwerpen & Alexandra Rehn & Alexander Graf & Johannes Christian Hellmuth & Alexandra Hollaus & Anne-Wiebe Mohr & Erik Gaitzsch & Tobias Weiglein & Enrico Georgi & Clemens , 2022. "Accumulation of mutations in antibody and CD8 T cell epitopes in a B cell depleted lymphoma patient with chronic SARS-CoV-2 infection," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    14. Adriana Tomic & Donal T. Skelly & Ane Ogbe & Daniel O’Connor & Matthew Pace & Emily Adland & Frances Alexander & Mohammad Ali & Kirk Allott & M. Azim Ansari & Sandra Belij-Rammerstorfer & Sagida Bibi , 2022. "Divergent trajectories of antiviral memory after SARS-CoV-2 infection," Nature Communications, Nature, vol. 13(1), pages 1-20, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-32216-0. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.