Human angiotensin-converting enzyme 2-specific antisense oligonucleotides reduce infection with SARS-CoV-2 variants.

Autor:	Lu T; Department of Otolaryngology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China; Otorhinolaryngology Institute of Sun Yat-sen University, Guangzhou, Guangdong, China; Guangzhou Key Laboratory of Otorhinolaryngology, Guangzhou, Guangdong, China., Zhang C; Department of Otolaryngology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China; Otorhinolaryngology Institute of Sun Yat-sen University, Guangzhou, Guangdong, China; Guangzhou Key Laboratory of Otorhinolaryngology, Guangzhou, Guangdong, China., Li Z; Department of Otolaryngology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China; Otorhinolaryngology Institute of Sun Yat-sen University, Guangzhou, Guangdong, China; Guangzhou Key Laboratory of Otorhinolaryngology, Guangzhou, Guangdong, China; Advanced Medical Technology Center, The First Affiliated Hospital, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, China., Wei Y; Department of Otolaryngology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China; Otorhinolaryngology Institute of Sun Yat-sen University, Guangzhou, Guangdong, China; Guangzhou Key Laboratory of Otorhinolaryngology, Guangzhou, Guangdong, China., Sadewasser A; Secarna Pharmaceuticals GmbH & Co. KG, Martinsried, Germany., Yan Y; Department of Otolaryngology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China; Otorhinolaryngology Institute of Sun Yat-sen University, Guangzhou, Guangdong, China; Guangzhou Key Laboratory of Otorhinolaryngology, Guangzhou, Guangdong, China., Sun L; Department of Otolaryngology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China; Otorhinolaryngology Institute of Sun Yat-sen University, Guangzhou, Guangdong, China; Guangzhou Key Laboratory of Otorhinolaryngology, Guangzhou, Guangdong, China., Li J; Department of Otolaryngology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China; Otorhinolaryngology Institute of Sun Yat-sen University, Guangzhou, Guangdong, China; Guangzhou Key Laboratory of Otorhinolaryngology, Guangzhou, Guangdong, China; Guangxi Hospital Division of The First Affiliated Hospital, Sun Yat-sen University, Nanning, China., Wen Y; Department of Otolaryngology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China; Otorhinolaryngology Institute of Sun Yat-sen University, Guangzhou, Guangdong, China; Guangzhou Key Laboratory of Otorhinolaryngology, Guangzhou, Guangdong, China., Lai S; Department of Otolaryngology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China; Otorhinolaryngology Institute of Sun Yat-sen University, Guangzhou, Guangdong, China; Guangzhou Key Laboratory of Otorhinolaryngology, Guangzhou, Guangdong, China., Chen C; Department of Otolaryngology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China; Otorhinolaryngology Institute of Sun Yat-sen University, Guangzhou, Guangdong, China; Guangzhou Key Laboratory of Otorhinolaryngology, Guangzhou, Guangdong, China., Zhong H; Department of Otolaryngology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China; Otorhinolaryngology Institute of Sun Yat-sen University, Guangzhou, Guangdong, China; Guangzhou Key Laboratory of Otorhinolaryngology, Guangzhou, Guangdong, China; Advanced Medical Technology Center, The First Affiliated Hospital, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, China., Jiménez MR; Secarna Pharmaceuticals GmbH & Co. KG, Martinsried, Germany., Klar R; Secarna Pharmaceuticals GmbH & Co. KG, Martinsried, Germany., Schell M; Secarna Pharmaceuticals GmbH & Co. KG, Martinsried, Germany., Raith S; Secarna Pharmaceuticals GmbH & Co. KG, Martinsried, Germany., Michel S; Secarna Pharmaceuticals GmbH & Co. KG, Martinsried, Germany., Ke B; Guangdong Provincial Center for Disease Control and Prevention, Guangzhou, Guangdong, China., Zheng H; Guangdong Provincial Center for Disease Control and Prevention, Guangzhou, Guangdong, China., Jaschinski F; Secarna Pharmaceuticals GmbH & Co. KG, Martinsried, Germany., Zhang N; Upper Airways Research Laboratory, Department of Oto-Rhino-Laryngology, Ghent University Hospital, Ghent, Belgium., Xiao H; Department of Endocrinology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China., Bachert C; Department of Otolaryngology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China; Department of Otorhinolaryngology - Head and Neck Surgery, University Hospital of Münster, Münster, Germany; Upper Airways Research Laboratory, Department of Oto-Rhino-Laryngology, Ghent University Hospital, Ghent, Belgium., Wen W; Department of Otolaryngology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China; Otorhinolaryngology Institute of Sun Yat-sen University, Guangzhou, Guangdong, China; Guangzhou Key Laboratory of Otorhinolaryngology, Guangzhou, Guangdong, China; Department of Otolaryngology, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China. Electronic address: wenwp@mail.sysu.edu.cn.
Jazyk:	angličtina
Zdroj:	The Journal of allergy and clinical immunology [J Allergy Clin Immunol] 2024 Oct; Vol. 154 (4), pp. 1044-1059. Date of Electronic Publication: 2024 Jun 21.
DOI:	10.1016/j.jaci.2024.06.007
Abstrakt:	Background: The Spike protein mutation severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) led to decreased protective effect of various vaccines and mAbs, suggesting that blocking SARS-CoV-2 infection by targeting host factors would make the therapy more resilient against virus mutations. Angiotensin-converting enzyme 2 (ACE2) is the host receptor of SARS-CoV-2 and its variants, as well as many other coronaviruses. Downregulation of ACE2 expression in the respiratory tract may prevent viral infection. Antisense oligonucleotides (ASOs) can be rationally designed on the basis of sequence data, require no delivery system, and can be administered locally. Objective: We sought to design ASOs that can block SARS-CoV-2 by downregulating ACE2 in human airway. Methods: ACE2-targeting ASOs were designed using a bioinformatic method and screened in cell lines. Human primary nasal epithelial cells cultured at the air-liquid interface and humanized ACE2 mice were used to detect the ACE2 reduction levels and the safety of ASOs. ASO-pretreated nasal epithelial cells and mice were infected and then used to detect the viral infection levels. Results: ASOs reduced ACE2 expression on mRNA and protein level in cell lines and in human nasal epithelial cells. Furthermore, they efficiently suppressed virus replication of 3 different SARS-CoV-2 variants in human nasal epithelial cells. In vivo, ASOs also downregulated human ACE2 in humanized ACE2 mice and thereby reduced viral load, histopathologic changes in lungs, and increased survival of mice. Conclusions: ACE2-targeting ASOs can effectively block SARS-CoV-2 infection. Our study provides a new approach for blocking SARS-CoV-2 and other ACE2-targeting virus in high-risk populations. Competing Interests: Disclosure statement This study was supported by Guangdong Research Program of Key Fields grant, National Natural Science Foundation of China grants, Natural Science Foundation of Guangdong Province grants, and Guangzhou Science and Technology Project of China grant. Disclosure of potential conflict of interest: The authors have filed patent applications for human angiotensin-converting enzyme 2–targeting antisense oligonucleotides and their activities in inhibiting severe acute respiratory syndrome coronavirus 2 infection. (Copyright © 2024. Published by Elsevier Inc.)
Databáze:	MEDLINE
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