A humanized mouse model for adeno-associated viral gene therapy.
Mercedes BarziTong ChenTrevor J GonzalezFrancis P PankowiczSeh Hoon OhHelen L StreffAlan RosalesYunhan MaSabrina ColliasSarah E WoodfieldAnna Mae DiehlSanjeev A VasudevanNhu Thao Nguyen GalvánJohn GossCharles A GersbachBeatrice Bissig-ChoisatAravind AsokanKarl-Dimiter BissigPublished in: Nature communications (2024)
Clinical translation of AAV-mediated gene therapy requires preclinical development across different experimental models, often confounded by variable transduction efficiency. Here, we describe a human liver chimeric transgene-free Il2rg -/- /Rag2 -/- /Fah -/- /Aavr -/- (TIRFA) mouse model overcoming this translational roadblock, by combining liver humanization with AAV receptor (AAVR) ablation, rendering murine cells impermissive to AAV transduction. Using human liver chimeric TIRFA mice, we demonstrate increased transduction of clinically used AAV serotypes in primary human hepatocytes compared to humanized mice with wild-type AAVR. Further, we demonstrate AAV transduction in human teratoma-derived primary cells and liver cancer tissue, displaying the versatility of the humanized TIRFA mouse. From a mechanistic perspective, our results support the notion that AAVR functions as both an entry receptor and an intracellular receptor essential for transduction. The TIRFA mouse should allow prediction of AAV gene transfer efficiency and the study of AAV vector biology in a preclinical human setting.
Keyphrases
- gene therapy
- endothelial cells
- mouse model
- wild type
- cell therapy
- induced apoptosis
- induced pluripotent stem cells
- pluripotent stem cells
- cell cycle arrest
- monoclonal antibody
- stem cells
- sars cov
- type diabetes
- mesenchymal stem cells
- cell death
- oxidative stress
- high fat diet induced
- endoplasmic reticulum stress
- signaling pathway
- metabolic syndrome
- genome wide
- liver injury