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J Allergy Clin Immunol
. 2024 Jun 21:S0091-6749(24)00631-6.
doi: 10.1016/j.jaci.2024.06.007. Online ahead of print. Human angiotensin converting enzyme 2 specific antisense oligonucleotides reduce infection with SARS-CoV-2 variants
Tong Lu 1 , Chengcheng Zhang 1 , Zhengqi Li 2 , Yi Wei 1 , Anne Sadewasser 3 , Yan Yan 1 , Lin Sun 1 , Jian Li 4 , Yihui Wen 1 , Shimin Lai 1 , Changhui Chen 1 , Hua Zhong 2 , Marta Reyes Jiménez 3 , Richard Klar 3 , Monika Schell 3 , Stefanie Raith 3 , Sven Michel 3 , Bixia Ke 5 , Huanying Zheng 5 , Frank Jaschinski 3 , Nan Zhang 6 , Haipeng Xiao 7 , Claus Bachert 8 , Weiping Wen 9
Affiliations
Background: The Spike protein mutation of SARS-CoV-2 led to decreased protective effect of various vaccines and monoclonal antibodies, 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. Down-regulation of ACE2 expression in the respiratory tract may prevent viral infection. Antisense oligonucleotides (ASOs) can be rationally designed based on sequence data, require no delivery system, and can be administered locally.
Objective: We sought to design ASOs that can block SARS-CoV-2 by down-regulating 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. ASOs 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 three different SARS-CoV-2 variants in human nasal epithelial cells. In vivo, ASOs also down-regulated human ACE2 in humanized ACE2 mice and thereby reduced viral load, histopathological changes in lungs, and they increased survival of mice.
Conclusion: 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.
Keywords: Angiotensin converting enzyme 2; Antisense oligonucleotides; COVID-19; SARS-CoV-2.
. 2024 Jun 21:S0091-6749(24)00631-6.
doi: 10.1016/j.jaci.2024.06.007. Online ahead of print. Human angiotensin converting enzyme 2 specific antisense oligonucleotides reduce infection with SARS-CoV-2 variants
Tong Lu 1 , Chengcheng Zhang 1 , Zhengqi Li 2 , Yi Wei 1 , Anne Sadewasser 3 , Yan Yan 1 , Lin Sun 1 , Jian Li 4 , Yihui Wen 1 , Shimin Lai 1 , Changhui Chen 1 , Hua Zhong 2 , Marta Reyes Jiménez 3 , Richard Klar 3 , Monika Schell 3 , Stefanie Raith 3 , Sven Michel 3 , Bixia Ke 5 , Huanying Zheng 5 , Frank Jaschinski 3 , Nan Zhang 6 , Haipeng Xiao 7 , Claus Bachert 8 , Weiping Wen 9
Affiliations
- PMID: 38909634
- DOI: 10.1016/j.jaci.2024.06.007
Background: The Spike protein mutation of SARS-CoV-2 led to decreased protective effect of various vaccines and monoclonal antibodies, 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. Down-regulation of ACE2 expression in the respiratory tract may prevent viral infection. Antisense oligonucleotides (ASOs) can be rationally designed based on sequence data, require no delivery system, and can be administered locally.
Objective: We sought to design ASOs that can block SARS-CoV-2 by down-regulating 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. ASOs 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 three different SARS-CoV-2 variants in human nasal epithelial cells. In vivo, ASOs also down-regulated human ACE2 in humanized ACE2 mice and thereby reduced viral load, histopathological changes in lungs, and they increased survival of mice.
Conclusion: 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.
Keywords: Angiotensin converting enzyme 2; Antisense oligonucleotides; COVID-19; SARS-CoV-2.