Generation of a Kupffer Cell-evading Adenovirus for Systemic and Liver-directed Gene Transfer

Authors

Reeti Khare, Mayo Graduate School, Rochester,
Shannon M. May, Mayo Clinic, Rochester
Francesco Vetrini, Baylor College of Medicine, Houston
Eric A. Weaver, University of Nebraska-Lincoln & Mayo Clinic, RochesterFollow
Donna Palmer, Baylor College of Medicine, Houston
Amanda Rosewell, Baylor College of Medicine, Houston
Nathan Grove, Baylor College of Medicine, Houston
Philip Ng, Baylor College of Medicine, HoustonFollow
Michael A. Barry, Mayo Clinic, RochesterFollow

Document Type

Article

Date of this Version

2011

Citation

Molecular Therapy 2011 Jul; 19(7): 1254–1262.

doi: 10.1038/mt.2011.71

Comments

The American Society of Gene & Cell Therapy

Abstract

As much as 90% of an intravenously (i.v.) injected dose of adenovirus serotype 5 (Ad5) is absorbed and destroyed by liver Kupffer cells. Viruses that escape these cells can then transduce hepatocytes after binding factor X (FX). Given that interactions with FX and Kupffer cells are thought to occur on the Ad5 hexon protein, we replaced its exposed hypervariable regions (HVR) with those from Ad6. When tested in vivo in BALB/c mice and in hamsters, the Ad5/6 chimera mediated >10 times higher transduction in the liver. This effect was not due to changes in FX binding. Rather, Ad5/6 appeared to escape Kupffer cell uptake as evidenced by producing no Kupffer cell death in vivo, not requiring predosing in vivo, and being phagocytosed less efficiently by macrophages in vitro compared to Ad5. When tested as a helper-dependent adenovirus (Ad) vec- tor, Ad5/6 mediated higher luciferase and factor IX trans- gene expression than either helper-dependent adenoviral 5 (HD-Ad5) or HD-Ad6 vectors. These data suggest that the Ad5/6 hexon-chimera evades Kupffer cells and may have utility for systemic and liver-directed therapies.