UMMS Affiliation

Department of Pediatrics, Division of Pediatric Pulmonology; Horae Gene Therapy Center; Program in Molecular Medicine

Publication Date


Document Type



Congenital, Hereditary, and Neonatal Diseases and Abnormalities | Digestive System Diseases | Genetics and Genomics | Medical Genetics | Therapeutics


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.


A1AT, AAT, AATD, AAV, RNAi, gene editing, humanized liver mouse model, liver regeneration, liver xenograft, miRNA, nuclease-free genome editing, shRNA, α-1 antitrypsin deficiency

Rights and Permissions

Copyright 2017 The Author(s).

DOI of Published Version



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 site

Journal/Book/Conference Title

Molecular therapy : the journal of the American Society of Gene Therapy

Related Resources

Link to Article in PubMed

PubMed ID


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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