Language
English
Publication Date
3-4-2024
Journal
Nature Communications
DOI
10.1038/s41467-024-46017-0
PMID
38438373
PMCID
PMC10912671
PubMedCentral® Posted Date
3-4-2024
PubMedCentral® Full Text Version
Post-print
Abstract
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.
Keywords
Humans, Animals, Mice, Liver, Dependovirus, Disease Models, Animal, Genetic Therapy, Hepatocytes, Mouse, Genetic engineering, Medical genetics, Gene therapy
Published Open-Access
yes
Recommended Citation
Barzi, Mercedes; Chen, Tong; Gonzalez, Trevor J; et al., "A Humanized Mouse Model for Adeno-Associated Viral Gene Therapy" (2024). Faculty, Staff and Students Publications. 8324.
https://digitalcommons.library.tmc.edu/baylor_docs/8324