Intranasal gene therapy to prevent infection by SARS-CoV-2 variants.

SARS-CoV-2 variants have emerged with enhanced pathogenicity and transmissibility, and escape from pre-existing immunity, suggesting first-generation vaccines and monoclonal antibodies may now be less effective. Here we present an approach for preventing clinical sequelae and the spread of SARS-CoV-...

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Autores principales:	Joshua J Sims, Jenny A Greig, Kristofer T Michalson, Sharon Lian, R Alexander Martino, Rosemary Meggersee, Kevin B Turner, Kalyani Nambiar, Cecilia Dyer, Christian Hinderer, Makoto Horiuchi, Hanying Yan, Xin Huang, Shu-Jen Chen, James M Wilson
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/1456eae8f81744b0b130542e55e5bbc3
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spelling	oai:doaj.org-article:1456eae8f81744b0b130542e55e5bbc32021-12-02T20:00:17ZIntranasal gene therapy to prevent infection by SARS-CoV-2 variants.1553-73661553-737410.1371/journal.ppat.1009544https://doaj.org/article/1456eae8f81744b0b130542e55e5bbc32021-07-01T00:00:00Zhttps://doi.org/10.1371/journal.ppat.1009544https://doaj.org/toc/1553-7366https://doaj.org/toc/1553-7374SARS-CoV-2 variants have emerged with enhanced pathogenicity and transmissibility, and escape from pre-existing immunity, suggesting first-generation vaccines and monoclonal antibodies may now be less effective. Here we present an approach for preventing clinical sequelae and the spread of SARS-CoV-2 variants. First, we affinity matured an angiotensin-converting enzyme 2 (ACE2) decoy protein, achieving 1000-fold binding improvements that extend across a wide range of SARS-CoV-2 variants and distantly related, ACE2-dependent coronaviruses. Next, we demonstrated the expression of this decoy in proximal airway when delivered via intranasal administration of an AAV vector. This intervention significantly diminished clinical and pathologic consequences of SARS-CoV-2 challenge in a mouse model and achieved therapeutic levels of decoy expression at the surface of proximal airways when delivered intranasally to nonhuman primates. Importantly, this long-lasting, passive protection approach is applicable in vulnerable populations such as the elderly and immune-compromised that do not respond well to traditional vaccination. This approach could be useful in combating COVID-19 surges caused by SARS-CoV-2 variants and should be considered as a countermeasure to future pandemics caused by one of the many pre-emergent, ACE2-dependent CoVs that are poised for zoonosis.Joshua J SimsJenny A GreigKristofer T MichalsonSharon LianR Alexander MartinoRosemary MeggerseeKevin B TurnerKalyani NambiarCecilia DyerChristian HindererMakoto HoriuchiHanying YanXin HuangShu-Jen ChenJames M WilsonPublic Library of Science (PLoS)articleImmunologic diseases. AllergyRC581-607Biology (General)QH301-705.5ENPLoS Pathogens, Vol 17, Iss 7, p e1009544 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
spellingShingle	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 Joshua J Sims Jenny A Greig Kristofer T Michalson Sharon Lian R Alexander Martino Rosemary Meggersee Kevin B Turner Kalyani Nambiar Cecilia Dyer Christian Hinderer Makoto Horiuchi Hanying Yan Xin Huang Shu-Jen Chen James M Wilson Intranasal gene therapy to prevent infection by SARS-CoV-2 variants.
description	SARS-CoV-2 variants have emerged with enhanced pathogenicity and transmissibility, and escape from pre-existing immunity, suggesting first-generation vaccines and monoclonal antibodies may now be less effective. Here we present an approach for preventing clinical sequelae and the spread of SARS-CoV-2 variants. First, we affinity matured an angiotensin-converting enzyme 2 (ACE2) decoy protein, achieving 1000-fold binding improvements that extend across a wide range of SARS-CoV-2 variants and distantly related, ACE2-dependent coronaviruses. Next, we demonstrated the expression of this decoy in proximal airway when delivered via intranasal administration of an AAV vector. This intervention significantly diminished clinical and pathologic consequences of SARS-CoV-2 challenge in a mouse model and achieved therapeutic levels of decoy expression at the surface of proximal airways when delivered intranasally to nonhuman primates. Importantly, this long-lasting, passive protection approach is applicable in vulnerable populations such as the elderly and immune-compromised that do not respond well to traditional vaccination. This approach could be useful in combating COVID-19 surges caused by SARS-CoV-2 variants and should be considered as a countermeasure to future pandemics caused by one of the many pre-emergent, ACE2-dependent CoVs that are poised for zoonosis.
format	article
author	Joshua J Sims Jenny A Greig Kristofer T Michalson Sharon Lian R Alexander Martino Rosemary Meggersee Kevin B Turner Kalyani Nambiar Cecilia Dyer Christian Hinderer Makoto Horiuchi Hanying Yan Xin Huang Shu-Jen Chen James M Wilson
author_facet	Joshua J Sims Jenny A Greig Kristofer T Michalson Sharon Lian R Alexander Martino Rosemary Meggersee Kevin B Turner Kalyani Nambiar Cecilia Dyer Christian Hinderer Makoto Horiuchi Hanying Yan Xin Huang Shu-Jen Chen James M Wilson
author_sort	Joshua J Sims
title	Intranasal gene therapy to prevent infection by SARS-CoV-2 variants.
title_short	Intranasal gene therapy to prevent infection by SARS-CoV-2 variants.
title_full	Intranasal gene therapy to prevent infection by SARS-CoV-2 variants.
title_fullStr	Intranasal gene therapy to prevent infection by SARS-CoV-2 variants.
title_full_unstemmed	Intranasal gene therapy to prevent infection by SARS-CoV-2 variants.
title_sort	intranasal gene therapy to prevent infection by sars-cov-2 variants.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/1456eae8f81744b0b130542e55e5bbc3
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Intranasal gene therapy to prevent infection by SARS-CoV-2 variants.

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