Survival Advantage of Both Human Hepatocyte Xenografts and Genome-Edited Hepatocytes for Treatment of alpha-1 Antitrypsin Deficiency
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Authors
Borel, FlorieTang, Qiushi
Gernoux, Gwladys
Greer, Cynthia
Wang, Ziqiong
Barzel, Adi
Kay, Mark A.
Shultz, Leonard D.
Greiner, Dale L.
Flotte, Terence R.
Brehm, Michael A.
Mueller, Christian
UMass Chan Affiliations
Program in Molecular MedicineHorae Gene Therapy Center
Department of Pediatrics, Division of Pediatric Pulmonology
Document Type
Journal ArticlePublication Date
2017-11-01Keywords
A1ATAAT
AATD
AAV
RNAi
gene editing
humanized liver mouse model
liver regeneration
liver xenograft
miRNA
nuclease-free genome editing
shRNA
α-1 antitrypsin deficiency
Congenital, Hereditary, and Neonatal Diseases and Abnormalities
Digestive System Diseases
Genetics and Genomics
Medical Genetics
Therapeutics
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Show full item recordAbstract
Hepatocytes represent an important target for gene therapy and editing of single-gene disorders. In alpha-1 antitrypsin (AAT) deficiency, one missense mutation results in impaired secretion of AAT. In most patients, lung damage occurs due to a lack of AAT-mediated protection of lung elastin from neutrophil elastase. In some patients, accumulation of misfolded PiZ mutant AAT protein triggers hepatocyte injury, leading to inflammation and cirrhosis. We hypothesized that correcting the Z mutant defect in hepatocytes would confer a selective advantage for repopulation of hepatocytes within an intact liver. A human PiZ allele was crossed onto an immune-deficient (NSG) strain to create a recipient strain (NSG-PiZ) for human hepatocyte xenotransplantation. Results indicate that NSG-PiZ recipients support heightened engraftment of normal human primary hepatocytes as compared with NSG recipients. This model can therefore be used to test hepatocyte cell therapies for AATD, but more broadly it serves as a simple, highly reproducible liver xenograft model. Finally, a promoterless adeno-associated virus (AAV) vector, expressing a wild-type AAT and a synthetic miRNA to silence the endogenous allele, was integrated into the albumin locus. This gene-editing approach leads to a selective advantage of edited hepatocytes, by silencing the mutant protein and augmenting normal AAT production, and improvement of the liver pathology.Source
Mol Ther. 2017 Nov 1;25(11):2477-2489. doi: 10.1016/j.ymthe.2017.09.020. Epub 2017 Sep 25. Link to article on publisher's siteDOI
10.1016/j.ymthe.2017.09.020Permanent Link to this Item
http://hdl.handle.net/20.500.14038/43614PubMed ID
29032169Related Resources
Link to Article in PubMedRights
Copyright 2017 The Author(s).Distribution License
http://creativecommons.org/licenses/by-nc-nd/4.0/ae974a485f413a2113503eed53cd6c53
10.1016/j.ymthe.2017.09.020