Rapid Generation of Circulating and Mucosal Decoy Human ACE2 using mRNA Nanotherapeutics for the Potential Treatment of SARS‐CoV‐2
Abstract Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) can cause lethal pulmonary damage in humans. It contains spike proteins on its envelope that bind to human angiotensin‐converting enzyme 2 (hACE2) expressed on airway cells, enabling entry of the virus, and causing infection. The...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2022-12-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202202556 |
| _version_ | 1811291013007802368 |
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| author | Jeonghwan Kim Antony Jozic Anindit Mukherjee Dylan Nelson Kevin Chiem Md Siddiqur Rahman Khan Jordi B. Torrelles Luis Martinez‐Sobrido Gaurav Sahay |
| author_facet | Jeonghwan Kim Antony Jozic Anindit Mukherjee Dylan Nelson Kevin Chiem Md Siddiqur Rahman Khan Jordi B. Torrelles Luis Martinez‐Sobrido Gaurav Sahay |
| author_sort | Jeonghwan Kim |
| collection | DOAJ |
| description | Abstract Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) can cause lethal pulmonary damage in humans. It contains spike proteins on its envelope that bind to human angiotensin‐converting enzyme 2 (hACE2) expressed on airway cells, enabling entry of the virus, and causing infection. The soluble form of hACE2 binds SARS‐CoV‐2 spike protein, prevents viral entry into target cells, and ameliorates lung injury; however, its short half‐life limits therapeutic utilities. Here, synthetic mRNA is engineered to encode a soluble form of hACE2 (hsACE2) to prevent viral infection. A novel lipid nanoparticle (LNP) is used for packaging and delivering mRNA to cells to produce hsACE2 proteins. Intravenously administered LNP delivers mRNA to hepatocytes, leading to the production of circulatory hsACE2 initiated within 2 h and sustained over several days. Inhaled LNP results in lung transfection and secretion of mucosal hsACE2 to lung epithelia, the primary site of entry and pathogenesis for SARS‐CoV‐2. Furthermore, mRNA‐generated hsACE2 binds to the receptor‐binding domain of the viral spike protein. Finally, hsACE2 effectively inhibits SARS‐CoV‐2 and its pseudoviruses from infecting host cells. The proof of principle study shows that mRNA‐based nanotherapeutics can be potentially deployed to neutralize SARS‐CoV‐2 and open new treatment opportunities for coronavirus disease 2019 (COVID‐19). |
| first_indexed | 2024-04-13T04:23:05Z |
| format | Article |
| id | doaj.art-6365935118ba4034b4c3d530945d734f |
| institution | Directory Open Access Journal |
| issn | 2198-3844 |
| language | English |
| last_indexed | 2024-04-13T04:23:05Z |
| publishDate | 2022-12-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj.art-6365935118ba4034b4c3d530945d734f2022-12-22T03:02:39ZengWileyAdvanced Science2198-38442022-12-01935n/an/a10.1002/advs.202202556Rapid Generation of Circulating and Mucosal Decoy Human ACE2 using mRNA Nanotherapeutics for the Potential Treatment of SARS‐CoV‐2Jeonghwan Kim0Antony Jozic1Anindit Mukherjee2Dylan Nelson3Kevin Chiem4Md Siddiqur Rahman Khan5Jordi B. Torrelles6Luis Martinez‐Sobrido7Gaurav Sahay8Department of Pharmaceutical Sciences College of Pharmacy Robertson Life Sciences Building Oregon State University Portland OR 97201 USADepartment of Pharmaceutical Sciences College of Pharmacy Robertson Life Sciences Building Oregon State University Portland OR 97201 USADepartment of Pharmaceutical Sciences College of Pharmacy Robertson Life Sciences Building Oregon State University Portland OR 97201 USADepartment of Pharmaceutical Sciences College of Pharmacy Robertson Life Sciences Building Oregon State University Portland OR 97201 USADisease Prevention and Intervention and Population Health Programs Texas Biomedical Research Institute San Antonio TX 78227 USADisease Prevention and Intervention and Population Health Programs Texas Biomedical Research Institute San Antonio TX 78227 USADisease Prevention and Intervention and Population Health Programs Texas Biomedical Research Institute San Antonio TX 78227 USADisease Prevention and Intervention and Population Health Programs Texas Biomedical Research Institute San Antonio TX 78227 USADepartment of Pharmaceutical Sciences College of Pharmacy Robertson Life Sciences Building Oregon State University Portland OR 97201 USAAbstract Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) can cause lethal pulmonary damage in humans. It contains spike proteins on its envelope that bind to human angiotensin‐converting enzyme 2 (hACE2) expressed on airway cells, enabling entry of the virus, and causing infection. The soluble form of hACE2 binds SARS‐CoV‐2 spike protein, prevents viral entry into target cells, and ameliorates lung injury; however, its short half‐life limits therapeutic utilities. Here, synthetic mRNA is engineered to encode a soluble form of hACE2 (hsACE2) to prevent viral infection. A novel lipid nanoparticle (LNP) is used for packaging and delivering mRNA to cells to produce hsACE2 proteins. Intravenously administered LNP delivers mRNA to hepatocytes, leading to the production of circulatory hsACE2 initiated within 2 h and sustained over several days. Inhaled LNP results in lung transfection and secretion of mucosal hsACE2 to lung epithelia, the primary site of entry and pathogenesis for SARS‐CoV‐2. Furthermore, mRNA‐generated hsACE2 binds to the receptor‐binding domain of the viral spike protein. Finally, hsACE2 effectively inhibits SARS‐CoV‐2 and its pseudoviruses from infecting host cells. The proof of principle study shows that mRNA‐based nanotherapeutics can be potentially deployed to neutralize SARS‐CoV‐2 and open new treatment opportunities for coronavirus disease 2019 (COVID‐19).https://doi.org/10.1002/advs.202202556COVID‐19gene therapyhuman soluble ACE2lipid nanoparticlesmessenger RNA |
| spellingShingle | Jeonghwan Kim Antony Jozic Anindit Mukherjee Dylan Nelson Kevin Chiem Md Siddiqur Rahman Khan Jordi B. Torrelles Luis Martinez‐Sobrido Gaurav Sahay Rapid Generation of Circulating and Mucosal Decoy Human ACE2 using mRNA Nanotherapeutics for the Potential Treatment of SARS‐CoV‐2 Advanced Science COVID‐19 gene therapy human soluble ACE2 lipid nanoparticles messenger RNA |
| title | Rapid Generation of Circulating and Mucosal Decoy Human ACE2 using mRNA Nanotherapeutics for the Potential Treatment of SARS‐CoV‐2 |
| title_full | Rapid Generation of Circulating and Mucosal Decoy Human ACE2 using mRNA Nanotherapeutics for the Potential Treatment of SARS‐CoV‐2 |
| title_fullStr | Rapid Generation of Circulating and Mucosal Decoy Human ACE2 using mRNA Nanotherapeutics for the Potential Treatment of SARS‐CoV‐2 |
| title_full_unstemmed | Rapid Generation of Circulating and Mucosal Decoy Human ACE2 using mRNA Nanotherapeutics for the Potential Treatment of SARS‐CoV‐2 |
| title_short | Rapid Generation of Circulating and Mucosal Decoy Human ACE2 using mRNA Nanotherapeutics for the Potential Treatment of SARS‐CoV‐2 |
| title_sort | rapid generation of circulating and mucosal decoy human ace2 using mrna nanotherapeutics for the potential treatment of sars cov 2 |
| topic | COVID‐19 gene therapy human soluble ACE2 lipid nanoparticles messenger RNA |
| url | https://doi.org/10.1002/advs.202202556 |
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