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Editing out five Serpina1 paralogs to create a mouse model of genetic emphysema

Chronic obstructive pulmonary disease affects 10% of the worldwide population, and the leading genetic cause is α-1 antitrypsin (AAT) deficiency. Due to the complexity of the murine locus, which includes up to six Serpina1 paralogs, no genetic animal model of the disease has been successfully genera...

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Autores principales: Borel, Florie, Sun, Huaming, Zieger, Marina, Cox, Andrew, Cardozo, Brynn, Li, Weiying, Oliveira, Gabriella, Davis, Airiel, Gruntman, Alisha, Flotte, Terence R., Brodsky, Michael H., Hoffman, Andrew M., Elmallah, Mai K., Mueller, Christian
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5856518/
https://www.ncbi.nlm.nih.gov/pubmed/29453277
http://dx.doi.org/10.1073/pnas.1713689115
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author Borel, Florie
Sun, Huaming
Zieger, Marina
Cox, Andrew
Cardozo, Brynn
Li, Weiying
Oliveira, Gabriella
Davis, Airiel
Gruntman, Alisha
Flotte, Terence R.
Brodsky, Michael H.
Hoffman, Andrew M.
Elmallah, Mai K.
Mueller, Christian
author_facet Borel, Florie
Sun, Huaming
Zieger, Marina
Cox, Andrew
Cardozo, Brynn
Li, Weiying
Oliveira, Gabriella
Davis, Airiel
Gruntman, Alisha
Flotte, Terence R.
Brodsky, Michael H.
Hoffman, Andrew M.
Elmallah, Mai K.
Mueller, Christian
author_sort Borel, Florie
collection PubMed
description Chronic obstructive pulmonary disease affects 10% of the worldwide population, and the leading genetic cause is α-1 antitrypsin (AAT) deficiency. Due to the complexity of the murine locus, which includes up to six Serpina1 paralogs, no genetic animal model of the disease has been successfully generated until now. Here we create a quintuple Serpina1a–e knockout using CRISPR/Cas9-mediated genome editing. The phenotype recapitulates the human disease phenotype, i.e., absence of hepatic and circulating AAT translates functionally to a reduced capacity to inhibit neutrophil elastase. With age, Serpina1 null mice develop emphysema spontaneously, which can be induced in younger mice by a lipopolysaccharide challenge. This mouse models not only AAT deficiency but also emphysema and is a relevant genetic model and not one based on developmental impairment of alveolarization or elastase administration. We anticipate that this unique model will be highly relevant not only to the preclinical development of therapeutics for AAT deficiency, but also to emphysema and smoking research.
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spelling pubmed-58565182018-04-06 Editing out five Serpina1 paralogs to create a mouse model of genetic emphysema Borel, Florie Sun, Huaming Zieger, Marina Cox, Andrew Cardozo, Brynn Li, Weiying Oliveira, Gabriella Davis, Airiel Gruntman, Alisha Flotte, Terence R. Brodsky, Michael H. Hoffman, Andrew M. Elmallah, Mai K. Mueller, Christian Proc Natl Acad Sci U S A Biological Sciences Chronic obstructive pulmonary disease affects 10% of the worldwide population, and the leading genetic cause is α-1 antitrypsin (AAT) deficiency. Due to the complexity of the murine locus, which includes up to six Serpina1 paralogs, no genetic animal model of the disease has been successfully generated until now. Here we create a quintuple Serpina1a–e knockout using CRISPR/Cas9-mediated genome editing. The phenotype recapitulates the human disease phenotype, i.e., absence of hepatic and circulating AAT translates functionally to a reduced capacity to inhibit neutrophil elastase. With age, Serpina1 null mice develop emphysema spontaneously, which can be induced in younger mice by a lipopolysaccharide challenge. This mouse models not only AAT deficiency but also emphysema and is a relevant genetic model and not one based on developmental impairment of alveolarization or elastase administration. We anticipate that this unique model will be highly relevant not only to the preclinical development of therapeutics for AAT deficiency, but also to emphysema and smoking research. National Academy of Sciences 2018-03-13 2018-02-16 /pmc/articles/PMC5856518/ /pubmed/29453277 http://dx.doi.org/10.1073/pnas.1713689115 Text en Copyright © 2018 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/ This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) .
spellingShingle Biological Sciences
Borel, Florie
Sun, Huaming
Zieger, Marina
Cox, Andrew
Cardozo, Brynn
Li, Weiying
Oliveira, Gabriella
Davis, Airiel
Gruntman, Alisha
Flotte, Terence R.
Brodsky, Michael H.
Hoffman, Andrew M.
Elmallah, Mai K.
Mueller, Christian
Editing out five Serpina1 paralogs to create a mouse model of genetic emphysema
title Editing out five Serpina1 paralogs to create a mouse model of genetic emphysema
title_full Editing out five Serpina1 paralogs to create a mouse model of genetic emphysema
title_fullStr Editing out five Serpina1 paralogs to create a mouse model of genetic emphysema
title_full_unstemmed Editing out five Serpina1 paralogs to create a mouse model of genetic emphysema
title_short Editing out five Serpina1 paralogs to create a mouse model of genetic emphysema
title_sort editing out five serpina1 paralogs to create a mouse model of genetic emphysema
topic Biological Sciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5856518/
https://www.ncbi.nlm.nih.gov/pubmed/29453277
http://dx.doi.org/10.1073/pnas.1713689115
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