ArticleMolecular therapy : the journal of the American Society of Gene Therapy2017
Survival Advantage of Both Human Hepatocyte Xenografts and Genome-Edited Hepatocytes for Treatment of α-1 Antitrypsin Deficiency.
Article in Molecular therapy : the journal of the American Society of Gene Therapy, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 50 papers.
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Who cites it
50 citing papers in PubMed.
- Hepatocyte-like cell therapy for end-stage liver disease: From basic science to clinical application.Liver research (Beijing, China) · 2026Review
- RNA editing for the treatment of alpha-1 antitrypsin deficiency.Nucleic acids research · 2026Article
- Review
- A compact base editor rescues AATD-associated liver and lung disease in mouse models.Molecular therapy : the journal of the American Society of Gene Therapy · 2025Article
- Serum factors create species-specific barriers to hepatic gene transfer by lipid nanoparticles in liver-humanized mice.Molecular therapy. Methods & clinical development · 2025Article
- Developing T Cell Epitope-Based Vaccines Against Infection: Challenging but Worthwhile.Vaccines · 2025Review
- Article
- Transient growth factor expression via mRNA in lipid nanoparticles promotes hepatocyte cell therapy in mice.Nature communications · 2024Article
- Ex vivo gene editing and cell therapy for hereditary tyrosinemia type 1.Hepatology communications · 2024Article
- Approaches to Therapeutic Gene Editing in Alpha-1 Antitrypsin Deficiency.Methods in molecular biology (Clifton, N.J.) · 2024Article
- Monitoring the Secretion and Activity of Alpha-1 Antitrypsin in Various Mammalian Cell Types.Methods in molecular biology (Clifton, N.J.) · 2024Article
- CRISPR-Cas9-mediated somatic correction of a one-base deletion in the Ugt1a gene ameliorates hyperbilirubinemia in Crigler-Najjar syndrome mice.Molecular therapy. Methods & clinical development · 2023Article
- A promoterless AAV6.2FF-based lung gene editing platform for the correction of surfactant protein B deficiency.Molecular therapy : the journal of the American Society of Gene Therapy · 2023Article
- Liver-Humanized NSG-PiZ Mice Support the Study of Chronic Hepatitis B Virus Infection and Antiviral Therapies.Microbiology spectrum · 2023Article
- Intrathymic AAV delivery results in therapeutic site-specific integration at TCR loci in mice.Blood · 2023Article
- Gene therapy for liver diseases - progress and challenges.Nature reviews. Gastroenterology & hepatology · 2023Review
- Human iPSC-hepatocyte modeling of alpha-1 antitrypsin heterozygosity reveals metabolic dysregulation and cellular heterogeneity.Cell reports · 2022Article
- Secretion of functional α1-antitrypsin is cell type dependent: Implications for intramuscular delivery for gene therapy.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Review
- Evaluation of cytosine base editing and adenine base editing as a potential treatment for alpha-1 antitrypsin deficiency.Molecular therapy : the journal of the American Society of Gene Therapy · 2022Article
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Authors and funding
12 authors.
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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.
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