Journal
SIGNAL TRANSDUCTION AND TARGETED THERAPY
Volume 7, Issue 1, Pages -Publisher
SPRINGERNATURE
DOI: 10.1038/s41392-022-01138-0
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Funding
- Health@InnoHK, Innovation and Technology Commission
- Government of the Hong Kong Special Administrative Region
- Health and Medical Research Fund, the Government of the Hong Kong Special Administrative Region [13]
- National Program on Key Research Project of China [2020YFA0707500]
- Theme-Based Research Scheme of the Research Grants Council [T11-709/21-N]
- Emergency Key Program of Guangzhou Laboratory [EKPG22-01]
- National Key Research and Development Programme on Public Security Risk Prevention and Control Emergency Project
- Health and Medical Research Fund [22210792]
- donations of Michael Seak-Kan Tong, Richard Yu and Carol Yu
- Lee Wan Keung Charity Foundation Limited
- May Tam Mak Mei Yin
- Respiratory Viral Research Foundation Limited
- Shaw Foundation Hong Kong, Hui Ming
- Hui Hoy and Chow Sin Lan Charity Fund Limited
- Chan Yin Chuen Memorial Charitable Foundation
- Chen Wai Wai Vivien Foundation Limited
- Marina Man-Wai Lee
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It has been found that the specially designed SARS-CoV-2 and influenza defective interfering genes (DIGs) can significantly inhibit the replication of corresponding viruses. Through the gene delivery vector TAT2-P1&LAH4, DIGs can be effectively delivered in the lungs to inhibit the replication of SARS-CoV-2 variants and influenza virus.
Defective interfering genes (DIGs) are short viral genomes and interfere with wild-type viral replication. Here, we demonstrate that the new designed SARS-CoV-2 DIG (CD3600) can significantly inhibit the replication of SARS-CoV-2 including Alpha, Delta, Kappa and Omicron variants in human HK-2 cells and influenza DIG (PAD4) can significantly inhibit influenza virus replication in human A549 cells. One dose of influenza DIGs prophylactically protects 90% mice from lethal challenge of A(H1N1)pdm09 virus and CD3600 inhibits SARS-CoV-2 replication in hamster lungs when DIGs are administrated to lungs one day before viral challenge. To further investigate the gene delivery vector in the respiratory tract, a peptidic TAT2-P1&LAH4, which can package genes to form small spherical nanoparticles with high endosomal escape ability, is demonstrated to dramatically increase gene expression in the lung airway. TAT2-P1&LAH4, with the dual-functional TAT2-P1 (gene-delivery and antiviral), can deliver CD3600 to significantly inhibit the replication of Delta and Omicron SARS-CoV-2 in hamster lungs. This peptide-based nanoparticle system can effectively transfect genes in lungs and deliver DIGs to inhibit SARS-CoV-2 variants and influenza virus in vivo, which provides the new insight into the drug delivery system for gene therapy against respiratory viruses.
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