UMMS Affiliation

Horae Gene Therapy Center; Department of Pediatrics, Division of Pediatric Pulmonology; Department of Molecular, Cell, and Cancer Biology

Publication Date

3-13-2018

Document Type

Article

Disciplines

Congenital, Hereditary, and Neonatal Diseases and Abnormalities | Genetic Phenomena | Genetics and Genomics | Medical Genetics | Respiratory Tract Diseases

Abstract

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.

Keywords

CRISPR, Serpina1, alpha-1 antitrypsin, emphysema, mouse model

Rights and Permissions

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

10.1073/pnas.1713689115

Source

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

Journal/Book/Conference Title

Proceedings of the National Academy of Sciences of the United States of America

Related Resources

Link to Article in PubMed

PubMed ID

29453277

Creative Commons License

Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.

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