A humanized mouse model for adeno-associated viral gene therapy

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...

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Bibliographic Details
Published in:	Nature communications Vol. 15; no. 1; p. 1955
Main Authors:	Barzi, Mercedes, Chen, Tong, Gonzalez, Trevor J., Pankowicz, Francis P., Oh, Seh Hoon, Streff, Helen L., Rosales, Alan, Ma, Yunhan, Collias, Sabrina, Woodfield, Sarah E., Diehl, Anna Mae, Vasudevan, Sanjeev A., Galvan, Thao N., Goss, John, Gersbach, Charles A., Bissig-Choisat, Beatrice, Asokan, Aravind, Bissig, Karl-Dimiter
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 04-03-2024 Nature Publishing Group Nature Portfolio
Subjects:	13 13/51 14 14/32 42 42/34 631/154/51/201 631/1647/334/1874/345 631/208/1516 631/61/17/1511 64 64/60 Ablation Animal models Animals Dependovirus - genetics Disease Models, Animal Gene therapy Genetic Therapy Hepatocytes Humanities and Social Sciences Humans Liver Liver cancer Mice multidisciplinary RAG2 protein Receptors Science Science (multidisciplinary) Serotypes Teratoma Transduction Transgenes
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Summary:	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. All natural AAV serotypes transduce murine hepatocytes more efficiently than their human counterparts in human liver chimeric mouse models. Here the authors developed a novel humanized mouse were human transduction of AAV can be studied.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2041-1723 2041-1723
DOI:	10.1038/s41467-024-46017-0