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Experimental Variables that Affect Human Hepatocyte AAV Transduction in Liver Chimeric Mice.
Zou, Chenhui; Vercauteren, Koen O A; Michailidis, Eleftherios; Kabbani, Mohammad; Zoluthkin, Irene; Quirk, Corrine; Chiriboga, Luis; Yazicioglu, Mustafa; Anguela, Xavier M; Meuleman, Philip; High, Katherine A; Herzog, Roland W; de Jong, Ype P.
Afiliação
  • Zou C; Division of Gastroenterology and Hepatology, Weill Cornell Medicine, New York, NY 10065, USA.
  • Vercauteren KOA; Laboratory of Virology and Infectious Disease, Rockefeller University, New York, NY 10065, USA.
  • Michailidis E; Laboratory of Virology and Infectious Disease, Rockefeller University, New York, NY 10065, USA.
  • Kabbani M; Laboratory of Liver Infectious Diseases, Ghent University, 9000 Ghent, Belgium.
  • Zoluthkin I; Laboratory of Virology and Infectious Disease, Rockefeller University, New York, NY 10065, USA.
  • Quirk C; Laboratory of Virology and Infectious Disease, Rockefeller University, New York, NY 10065, USA.
  • Chiriboga L; Department of Pediatrics, University of Florida College of Medicine, Gainesville, FL 32603, USA.
  • Yazicioglu M; Laboratory of Virology and Infectious Disease, Rockefeller University, New York, NY 10065, USA.
  • Anguela XM; Department of Pathology, NYU Langone Health, New York, NY 10016, USA.
  • Meuleman P; Spark Therapeutics, Philadelphia, PA 19104, USA.
  • High KA; Spark Therapeutics, Philadelphia, PA 19104, USA.
  • Herzog RW; Laboratory of Liver Infectious Diseases, Ghent University, 9000 Ghent, Belgium.
  • de Jong YP; Spark Therapeutics, Philadelphia, PA 19104, USA.
Mol Ther Methods Clin Dev ; 18: 189-198, 2020 Sep 11.
Article em En | MEDLINE | ID: mdl-32637450
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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Tipo de estudo: Prognostic_studies Idioma: En Revista: Mol Ther Methods Clin Dev Ano de publicação: 2020 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Tipo de estudo: Prognostic_studies Idioma: En Revista: Mol Ther Methods Clin Dev Ano de publicação: 2020 Tipo de documento: Article