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Experimental Variables that Affect Human Hepatocyte AAV Transduction in Liver Chimeric Mice.

Abstract：

:Adeno-associated virus (AAV) vector serotypes vary in their ability to transduce hepatocytes from different species. Chimeric mouse models harboring human hepatocytes have shown translational promise for liver-directed gene therapies. However, many variables that influence human hepatocyte transduction and transgene expression in such models remain poorly defined. Here, we aimed to test whether three experimental conditions influence AAV transgene expression in immunodeficient, fumaryl-acetoactetate-hydrolase-deficient (Fah-/-) chimeric mice repopulated with primary human hepatocytes. We examined the effects of the murine liver injury cycle, human donor variability, and vector doses on hepatocyte transduction with various AAV serotypes expressing a green fluorescent protein (GFP). We determined that the timing of AAV vector challenge in the liver injury cycle resulted in up to 7-fold differences in the percentage of GFP expressing human hepatocytes. The GFP+ hepatocyte frequency varied 7-fold between human donors without, however, changing the relative transduction efficiency between serotypes for an individual donor. There was also a clear relationship between AAV vector doses and human hepatocyte transduction and transgene expression. We conclude that several experimental variables substantially affect human hepatocyte transduction in the Fah-/- chimera model, attention to which may improve reproducibility between findings from different laboratories.

journal_name

Mol Ther Methods Clin Dev

journal_title

Molecular therapy. Methods & clinical development

authors

Zou C,Vercauteren KOA,Michailidis E,Kabbani M,Zoluthkin I,Quirk C,Chiriboga L,Yazicioglu M,Anguela XM,Meuleman P,High KA,Herzog RW,de Jong YP

doi

10.1016/j.omtm.2020.05.033

subject

Has Abstract

pub_date

2020-06-02 00:00:00

pages

189-198

issn

2329-0501

pii

S2329-0501(20)30120-0

journal_volume

18

pub_type

杂志文章

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