Generation of a kupffer cell-evading adenovirus for systemic and liver-directed gene transfer

Reeti Khare, Shannon M. May, Francesco Vetrini, Eric A. Weaver, Donna Palmer, Amanda Rosewell, Nathan Grove, Philip Ng, Michael A. Barry

Research output: Contribution to journalArticlepeer-review

53 Scopus citations

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) vector, Ad5/6 mediated higher luciferase and factor IX transgene 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.

Original languageEnglish (US)
Pages (from-to)1254-1262
Number of pages9
JournalMolecular Therapy
Volume19
Issue number7
DOIs
StatePublished - Jul 2011

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery

Fingerprint Dive into the research topics of 'Generation of a kupffer cell-evading adenovirus for systemic and liver-directed gene transfer'. Together they form a unique fingerprint.

Cite this