A humanized mouse model for adeno-associated viral gene therapy

Mercedes Barzi, Tong Chen, Trevor J. Gonzalez, Francis P. Pankowicz, Seh Hoon Oh, Helen L. Streff, Alan Rosales, Yunhan Ma, Sabrina Collias, Sarah E. Woodfield, Anna Mae Diehl, Sanjeev A. Vasudevan, Thao N. Galvan, John Goss, Charles A. Gersbach, Beatrice Bissig-Choisat, Aravind Asokan and Karl-Dimiter Bissig ()
Additional contact information
Mercedes Barzi: Duke University Medical Center
Tong Chen: Duke University Medical Center
Trevor J. Gonzalez: Duke University Medical Center
Francis P. Pankowicz: Baylor College of Medicine
Seh Hoon Oh: Duke University Medical Center
Helen L. Streff: Duke University Pratt School of Engineering, Duke University
Alan Rosales: Duke University Pratt School of Engineering, Duke University
Yunhan Ma: Duke University Medical Center
Sabrina Collias: Duke University Medical Center
Sarah E. Woodfield: Baylor College of Medicine
Anna Mae Diehl: Duke University Medical Center
Sanjeev A. Vasudevan: Baylor College of Medicine
Thao N. Galvan: Texas Children’s Hospital
John Goss: Texas Children’s Hospital
Charles A. Gersbach: Duke University Pratt School of Engineering, Duke University
Beatrice Bissig-Choisat: Duke University Medical Center
Aravind Asokan: Duke University Medical Center
Karl-Dimiter Bissig: Duke University Medical Center

Nature Communications, 2024, vol. 15, issue 1, 1-10

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-46017-0

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