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Human angiotensin-converting enzyme 2–specific antisense oligonucleotides reduce infection with SARS-CoV-2 variants - 03/10/24

Doi : 10.1016/j.jaci.2024.06.007 
Tong Lu, MD a, b, c, , Chengcheng Zhang, PhD a, b, c, , Zhengqi Li, MD a, b, c, e, , Yi Wei, PhD a, b, c, , Anne Sadewasser, PhD k, , Yan Yan, MD a, b, c, Lin Sun, MD a, b, c, Jian Li, MD, PhD a, b, c, f, Yihui Wen, MD, PhD a, b, c, Shimin Lai, MD a, b, c, Changhui Chen, MD a, b, c, Hua Zhong, MD, PhD a, b, c, e, Marta Reyes Jiménez, PhD k, Richard Klar, PhD k, Monika Schell, PhD k, Stefanie Raith, PhD k, Sven Michel, PhD k, Bixia Ke, MS j, Huanying Zheng, BS j, Frank Jaschinski, PhD k, Nan Zhang, MD, PhD h, Haipeng Xiao, MD, PhD i, Claus Bachert, MD, PhD a, g, h, Weiping Wen, MD, PhD a, b, c, d,
a Department of Otolaryngology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China 
b Otorhinolaryngology Institute of Sun Yat-sen University, Guangzhou, Guangdong, China 
c Guangzhou Key Laboratory of Otorhinolaryngology, Guangzhou, Guangdong, China 
d Department of Otolaryngology, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China 
e Advanced Medical Technology Center, The First Affiliated Hospital, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, China 
f Guangxi Hospital Division of The First Affiliated Hospital, Sun Yat-sen University, Nanning, China 
g Department of Otorhinolaryngology - Head and Neck Surgery, University Hospital of Münster, Münster, Germany 
h Upper Airways Research Laboratory, Department of Oto-Rhino-Laryngology, Ghent University Hospital, Ghent, Belgium 
j Guangdong Provincial Center for Disease Control and Prevention, Guangzhou, Guangdong, China 
i Department of Endocrinology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China 
k Secarna Pharmaceuticals GmbH & Co. KG, Martinsried, Germany 

Corresponding author: Weiping Wen, MD, PhD, Department of Otolaryngology, The First Affiliated Hospital of Sun Yat-sen University, Zhongshan 2nd Road, Guangzhou, Guangdong, P.R. China.Department of OtolaryngologyThe First Affiliated Hospital of Sun Yat-sen UniversityZhongshan 2nd RoadGuangzhouGuangdongP.R. China

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Abstract

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.

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Key words : Angiotensin-converting enzyme 2, antisense oligonucleotides, SARS-CoV-2, COVID-19

Abbreviations used : ACE2, ALI, ASO, COVID-19, dpi, hACE2, hNEC, HPRT1, HRP, IC50, LNA, NTC, SARS-CoV-2, SYSU, N gene, ORF gene, TCID50, TLR9, TMPRSS2, UNT, WB


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Vol 154 - N° 4

P. 1044-1059 - octobre 2024 Regresar al número
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