Document Type
Article
Publication Date
11-1-2017
JAX Source
Mol Ther 2017 Nov 1; 25(11):2477-2489.
Volume
25
Issue
11
First Page
2477
Last Page
2489
ISSN
1525-0024
PMID
29032169
DOI
https://doi.org/10.1016/j.ymthe.2017.09.020
Grant
OD018259, CA034196
Abstract
Hepatocytes represent an important target for gene therapy and editing of single-gene disorders. In α-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. Mol Ther 2017 Nov 1; 25(11):2477-2489.
Recommended Citation
Borel F,
Tang Q,
Gernoux G,
Greer C,
Wang Z,
Barzel A,
Kay M,
Shultz LD,
Greiner D,
Flotte T,
Brehm M,
Mueller C.
Survival Advantage of Both Human Hepatocyte Xenografts and Genome-Edited Hepatocytes for Treatment of α-1 Antitrypsin Deficiency. Mol Ther 2017 Nov 1; 25(11):2477-2489.