An intranasal ASO therapeutic targeting SARS-CoV-2.

Autor:	Zhu C; Department of Nutritional Sciences & Toxicology, University of California, Berkeley, CA, USA.; Innovative Genomics Institute, University of California, Berkeley, CA, USA., Lee JY; Department of Nutritional Sciences & Toxicology, University of California, Berkeley, CA, USA.; Innovative Genomics Institute, University of California, Berkeley, CA, USA., Woo JZ; Whitehead Institute for Biomedical Research, Cambridge, MA, USA.; Department of Microbiology, Harvard Medical School, Boston, MA, USA., Xu L; Department of Nutritional Sciences & Toxicology, University of California, Berkeley, CA, USA.; Innovative Genomics Institute, University of California, Berkeley, CA, USA., Nguyenla X; Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, Berkeley, CA, USA., Yamashiro LH; Department of Molecular and Cell Biology, Division of Immunology and Pathogenesis, University of California, Berkeley, CA, USA., Ji F; Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA., Biering SB; Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, Berkeley, CA, USA., Van Dis E; Department of Molecular and Cell Biology, Division of Immunology and Pathogenesis, University of California, Berkeley, CA, USA., Gonzalez F; Department of Nutritional Sciences & Toxicology, University of California, Berkeley, CA, USA.; Innovative Genomics Institute, University of California, Berkeley, CA, USA., Fox D; Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, Berkeley, CA, USA., Wehri E; The Henry Wheeler Center for Emerging and Neglected Diseases, University of California, Berkeley, CA, USA., Rustagi A; Department of Medicine, Division of Infectious Diseases and Geographic Medicine, Stanford University, School of Medicine, Stanford, CA, USA., Pinsky BA; Department of Medicine, Division of Infectious Diseases and Geographic Medicine, Stanford University, School of Medicine, Stanford, CA, USA.; Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA., Schaletzky J; The Henry Wheeler Center for Emerging and Neglected Diseases, University of California, Berkeley, CA, USA., Blish CA; Department of Medicine, Division of Infectious Diseases and Geographic Medicine, Stanford University, School of Medicine, Stanford, CA, USA., Chiu C; Department of Laboratory Medicine, University of California, San Francisco, CA, USA., Harris E; Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, Berkeley, CA, USA., Sadreyev RI; Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA., Stanley S; Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, Berkeley, CA, USA.; Department of Molecular and Cell Biology, Division of Immunology and Pathogenesis, University of California, Berkeley, CA, USA., Kauppinen S; Center for RNA Medicine, Aalborg University, Copenhagen, Denmark., Rouskin S; Whitehead Institute for Biomedical Research, Cambridge, MA, USA.; Department of Microbiology, Harvard Medical School, Boston, MA, USA., Näär AM; Department of Nutritional Sciences & Toxicology, University of California, Berkeley, CA, USA. naar@berkeley.edu.; Innovative Genomics Institute, University of California, Berkeley, CA, USA. naar@berkeley.edu.
Jazyk:	angličtina
Zdroj:	Nature communications [Nat Commun] 2022 Aug 03; Vol. 13 (1), pp. 4503. Date of Electronic Publication: 2022 Aug 03.
DOI:	10.1038/s41467-022-32216-0
Abstrakt:	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. (© 2022. The Author(s).)
Databáze:	MEDLINE
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