Horae Gene Therapy Center; Department of Pediatrics, Division of Pediatric Pulmonology; Department of Molecular, Cell, and Cancer Biology
Congenital, Hereditary, and Neonatal Diseases and Abnormalities | Genetic Phenomena | Genetics and Genomics | Medical Genetics | Respiratory Tract Diseases
Chronic obstructive pulmonary disease affects 10% of the worldwide population, and the leading genetic cause is alpha-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.
CRISPR, Serpina1, alpha-1 antitrypsin, emphysema, mouse model
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Copyright © 2018 the Author(s). Published by PNAS. This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND).
DOI of Published Version
Proc Natl Acad Sci U S A. 2018 Mar 13;115(11):2788-2793. doi: 10.1073/pnas.1713689115. Epub 2018 Feb 16. Link to article on publisher's site
Proceedings of the National Academy of Sciences of the United States of America
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.; and Mueller, Christian, "Editing out five Serpina1 paralogs to create a mouse model of genetic emphysema" (2018). Pediatric Publications and Presentations. 199.
Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.