ArticleMolecular therapy : the journal of the American Society of Gene Therapy2021
ZFN-mediated in vivo gene editing in hepatocytes leads to supraphysiologic α-Gal A activity and effective substrate reduction in Fabry mice.
Article in Molecular therapy : the journal of the American Society of Gene Therapy, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 22 citations in OpenAlex.
- Pathophysiological mechanisms of organ injury in Fabry disease: Update via multi-omics.Genes & diseases · 2026Review
- Harnessing myostatin pleiotropy for multitrait improvement via precision gene editing.Frontiers in genome editing · 2026Review
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- Genomic medicine in hepatology: mechanisms and liver treatment strategies.Molecular medicine (Cambridge, Mass.) · 2025Review
- Validation of caprine H11 and the Rosa26 platform for transgene integration via CRISPR-based system: investigations on stable transgene expression and genetic biosafety.Functional & integrative genomics · 2025Article
- Current trends in gene therapy to treat inherited disorders of the brain.Molecular therapy : the journal of the American Society of Gene Therapy · 2025Review
- Rescue of lysosomal acid lipase deficiency in mice by rAAV8 liver gene transfer.Communications medicine · 2025Article
- Genetic engineering frontiers in cell manipulation-based tissue engineering: A comprehensive review.BioImpacts : BI · 2025Review
- Precise genome-editing in human diseases: mechanisms, strategies and applications.Signal transduction and targeted therapy · 2024Review
- Review
- Production of therapeutic levels of human FIX-R338L by engineered B cells using GMP-compatible medium.Molecular therapy. Methods & clinical development · 2023Article
- Activation of mitochondrial TRAP1 stimulates mitochondria-lysosome crosstalk and correction of lysosomal dysfunction.iScience · 2022Article
- mRNA and gene editing: Late breaking therapies in liver diseases.Hepatology (Baltimore, Md.) · 2022Review
- Autologous, lentivirus-modified, T-rapa cell "micropharmacies" for lysosomal storage disorders.EMBO molecular medicine · 2022Article
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11 authors at 2 institutions in 1 country.
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Abstract
Fabry disease, a lysosomal storage disorder resulting from the deficient activity of α-galactosidase A (α-Gal A), is characterized by cardiac, renal, and/or cerebrovascular disease due to progressive accumulation of the enzyme's substrates, globotriaosylceramide (Gb3) and globotriaosylsphingosine (Lyso-Gb3). We report here the preclinical evaluation of liver-targeted in vivo genome editing using zinc-finger nuclease (ZFN) technology to insert the human α-galactosidase A (hGLA) cDNA into the albumin "safe harbor" locus of Fabry mice, thereby generating an albumin-α-Gal A fusion protein. The mature α-Gal A protein is secreted into the circulation for subsequent mannose-6-phosphate receptor-mediated tissue uptake. Donor vector optimization studies showed that replacing the hGLA cDNA signal peptide sequence with that of human iduronate 2-sulfatase (IDS) achieved higher transgene expression. Intravenous adeno-associated virus (AAV) 2/8-mediated co-delivery of the IDS-hGLA donor and ZFNs targeting the albumin locus resulted in continuous, supraphysiological plasma and tissue α-Gal A activities, which essentially normalized Gb3 and Lyso-Gb3 levels in key tissues of pathology. Notably, this was achieved with <10% of hepatocytes being edited to express hGLA, occurring mostly via non-homologous end joining (NHEJ) rather than homology-directed repair (HDR). These studies indicate that ZFN-mediated in vivo genome editing has the potential to be an effective one-time therapy for Fabry disease.
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