July 19, 2019  |  

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

Authors: Borel, Florie and Sun, Huaming and Zieger, Marina and Cox, Andrew and Cardozo, Brynn and Li, Weiying and Oliveira, Gabriella and Davis, Airiel and Gruntman, Alisha and Flotte, Terence R and Brodsky, Michael H and Hoffman, Andrew M and Elmallah, Mai K and Mueller, Christian

Chronic obstructive pulmonary disease affects 10% of the worldwide population, and the leading genetic cause is a-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. Copyright © 2018 the Author(s). Published by PNAS.

Journal: Proceedings of the National Academy of Sciences of the United States of America
DOI: 10.1073/pnas.1713689115
Year: 2018

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