An intranasal ASO therapeutic targeting SARS-CoV-2

• Published in: Nature communications Vol. 13; no. 1; pp. 4503 - 13
• Main Authors: Zhu, Chi, Lee, Justin Y., Woo, Jia Z., Xu, Lei, Wrynla, Xammy Huu, Yamashiro, Livia H., Ji, Fei, Biering, Scott B., Van Dis, Erik, Gonzalez, Federico, Fox, Douglas, Wehri, Eddie, Rustagi, Arjun, Pinsky, Benjamin A., Schaletzky, Julia, Blish, Catherine A., Chiu, Charles, Harris, Eva, Sadreyev, Ruslan I., Stanley, Sarah, Kauppinen, Sakari, Rouskin, Silvi, Näär, Anders M.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 03.08.2022; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/1; 13/106; 13/109; 13/51; 14; 14/1; 14/5; 14/63; 38; 38/89; 38/90; 38/91; 49; 59; 631/326/596; 64; 64/60; 692/308/153; Administration, Intranasal; Animals; Antibodies; Antisense oligonucleotides; Antiviral drugs; Conserved sequence; Coronaviruses; COVID-19; Disease transmission; Gene sequencing; Humanities and Social Sciences; Humans; Infections; Infectivity; Intranasal administration; Lungs; Mice; multidisciplinary; Nucleic acids; Nucleotide sequence; Oligonucleotides; Oligonucleotides, Antisense - pharmacology; Oligonucleotides, Antisense - therapeutic use; Pandemics; Pandemics - prevention & control; Replication; Ribonucleic acid; RNA; RNA, Viral - genetics; SARS-CoV-2; Science; Science (multidisciplinary); Severe acute respiratory syndrome coronavirus 2; Therapeutic targets; Vaccines; Viral diseases; Viral infections
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-32216-0

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. Despite approved vaccines and anti-virals to prevent and treat SARS-CoV-2 infection, there is a need for further development of efficient antiviral therapeutic strategy. Here, Zhu et al. develop locked nucleic acid antisense oligonucleotides (LNA ASOs) targeting the 5’ leader sequence of SARS-CoV-2 RNA to interfere with replication of wildtype virus and variants of concern. Daily intranasal administration in K18-hACE2 humanized mice suppresses viral infection in lung.