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Proc Natl Acad Sci U S A. 2018 Mar 13;115(11):2788-2793. doi: 10.1073/pnas.1713689115. Epub 2018 Feb 16.

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

Author information

1
Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, MA 01605.
2
Cummings School of Veterinary Medicine, Tufts University, Grafton, MA 01536.
3
Department of Pediatrics, University of Massachusetts Medical School, Worcester, MA 01605.
4
Department of Molecular, Cell, and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605.
5
Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, MA 01605; chris.mueller@umassmed.edu.

Abstract

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.

KEYWORDS:

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

Comment in

PMID:
29453277
PMCID:
PMC5856518
DOI:
10.1073/pnas.1713689115
[Indexed for MEDLINE]
Free PMC Article

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