Rapid Generation of Circulating and Mucosal Decoy Human ACE2 using mRNA Nanotherapeutics for the Potential Treatment of SARS-CoV-2.
COVID-19
gene therapy
human soluble ACE2
lipid nanoparticles
messenger RNA
Journal
Advanced science (Weinheim, Baden-Wurttemberg, Germany)
ISSN: 2198-3844
Titre abrégé: Adv Sci (Weinh)
Pays: Germany
ID NLM: 101664569
Informations de publication
Date de publication:
12 2022
12 2022
Historique:
revised:
19
09
2022
received:
06
05
2022
pubmed:
11
10
2022
medline:
22
12
2022
entrez:
10
10
2022
Statut:
ppublish
Résumé
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).
Identifiants
pubmed: 36216580
doi: 10.1002/advs.202202556
pmc: PMC9762296
doi:
Substances chimiques
Angiotensin-Converting Enzyme 2
EC 3.4.17.23
spike protein, SARS-CoV-2
0
RNA, Messenger
0
Lipid Nanoparticles
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
e2202556Subventions
Organisme : NHLBI NIH HHS
ID : R01 HL146736
Pays : United States
Organisme : National Heart Lung and Blood Institute (NHLBI)
ID : 1R01HL146736-01 (G.S)
Organisme : Cystic Fibrosis Foundation
ID : SAHAY19XX0
Organisme : Cystic Fibrosis Foundation
ID : SAHAY18G0 (G.S)
Commentaires et corrections
Type : UpdateOf
Informations de copyright
© 2022 The Authors. Advanced Science published by Wiley-VCH GmbH.
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