| Autor: |
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, Karl-Dimiter Bissig |
| Jazyk: |
angličtina |
| Rok vydání: |
2024 |
| Předmět: |
|
| Zdroj: |
Nature Communications, Vol 15, Iss 1, Pp 1-10 (2024) |
| Druh dokumentu: |
article |
| ISSN: |
2041-1723 |
| DOI: |
10.1038/s41467-024-46017-0 |
| Popis: |
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. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
|
Full text from SpringerLink