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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| Format: | Article |
| Language: | English |
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Nature Portfolio
2022-08-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-022-32216-0 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Chi Zhu |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-465980a86b3646a5914f997d2bfea608 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2022-08-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-465980a86b3646a5914f997d2bfea6082025-08-20T04:01:36ZengNature PortfolioNature Communications2041-17232022-08-0113111310.1038/s41467-022-32216-0An intranasal ASO therapeutic targeting SARS-CoV-2Chi Zhu0Justin Y. Lee1Jia Z. Woo2Lei Xu3Xammy Huu Wrynla4Livia H. Yamashiro5Fei Ji6Scott B. Biering7Erik Van Dis8Federico Gonzalez9Douglas Fox10Eddie Wehri11Arjun Rustagi12Benjamin A. Pinsky13Julia Schaletzky14Catherine A. Blish15Charles Chiu16Eva Harris17Ruslan I. Sadreyev18Sarah Stanley19Sakari Kauppinen20Silvi Rouskin21Anders M. Näär22Department of Nutritional Sciences & Toxicology, University of CaliforniaDepartment of Nutritional Sciences & Toxicology, University of CaliforniaWhitehead Institute for Biomedical ResearchDepartment of Nutritional Sciences & Toxicology, University of CaliforniaDivision of Infectious Diseases and Vaccinology, School of Public Health, University of California, BerkeleyDepartment of Molecular and Cell Biology, Division of Immunology and Pathogenesis, University of CaliforniaDepartment of Molecular Biology, Massachusetts General HospitalDivision of Infectious Diseases and Vaccinology, School of Public Health, University of California, BerkeleyDepartment of Molecular and Cell Biology, Division of Immunology and Pathogenesis, University of CaliforniaDepartment of Nutritional Sciences & Toxicology, University of CaliforniaDivision of Infectious Diseases and Vaccinology, School of Public Health, University of California, BerkeleyThe Henry Wheeler Center for Emerging and Neglected Diseases, University of CaliforniaDepartment of Medicine, Division of Infectious Diseases and Geographic Medicine, Stanford University, School of MedicineDepartment of Medicine, Division of Infectious Diseases and Geographic Medicine, Stanford University, School of MedicineThe Henry Wheeler Center for Emerging and Neglected Diseases, University of CaliforniaDepartment of Medicine, Division of Infectious Diseases and Geographic Medicine, Stanford University, School of MedicineDepartment of Laboratory Medicine, University of CaliforniaDivision of Infectious Diseases and Vaccinology, School of Public Health, University of California, BerkeleyDepartment of Molecular Biology, Massachusetts General HospitalDivision of Infectious Diseases and Vaccinology, School of Public Health, University of California, BerkeleyCenter for RNA Medicine, Aalborg UniversityWhitehead Institute for Biomedical ResearchDepartment of Nutritional Sciences & Toxicology, University of CaliforniaAbstract 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.https://doi.org/10.1038/s41467-022-32216-0 |
| spellingShingle | 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 An intranasal ASO therapeutic targeting SARS-CoV-2 Nature Communications |
| title | An intranasal ASO therapeutic targeting SARS-CoV-2 |
| title_full | An intranasal ASO therapeutic targeting SARS-CoV-2 |
| title_fullStr | An intranasal ASO therapeutic targeting SARS-CoV-2 |
| title_full_unstemmed | An intranasal ASO therapeutic targeting SARS-CoV-2 |
| title_short | An intranasal ASO therapeutic targeting SARS-CoV-2 |
| title_sort | intranasal aso therapeutic targeting sars cov 2 |
| url | https://doi.org/10.1038/s41467-022-32216-0 |
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