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 journalArticle

45 Citations (Scopus)

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

Fingerprint

Kupffer Cells
Adenoviridae
Liver
Factor X
Genes
Factor IX
Serogroup
Luciferases
Transgenes
Phagocytosis
Cricetinae
Hepatocytes
Cell Death
Macrophages
Viruses

ASJC Scopus subject areas

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

Cite this

Khare, R., May, S. M., Vetrini, F., Weaver, E. A., Palmer, D., Rosewell, A., ... Barry, M. A. (2011). Generation of a kupffer cell-evading adenovirus for systemic and liver-directed gene transfer. Molecular Therapy, 19(7), 1254-1262. https://doi.org/10.1038/mt.2011.71

Generation of a kupffer cell-evading adenovirus for systemic and liver-directed gene transfer. / Khare, Reeti; May, Shannon M.; Vetrini, Francesco; Weaver, Eric A.; Palmer, Donna; Rosewell, Amanda; Grove, Nathan; Ng, Philip; Barry, Michael A.

In: Molecular Therapy, Vol. 19, No. 7, 07.2011, p. 1254-1262.

Research output: Contribution to journalArticle

Khare, R, May, SM, Vetrini, F, Weaver, EA, Palmer, D, Rosewell, A, Grove, N, Ng, P & Barry, MA 2011, 'Generation of a kupffer cell-evading adenovirus for systemic and liver-directed gene transfer', Molecular Therapy, vol. 19, no. 7, pp. 1254-1262. https://doi.org/10.1038/mt.2011.71
Khare, Reeti ; May, Shannon M. ; Vetrini, Francesco ; Weaver, Eric A. ; Palmer, Donna ; Rosewell, Amanda ; Grove, Nathan ; Ng, Philip ; Barry, Michael A. / Generation of a kupffer cell-evading adenovirus for systemic and liver-directed gene transfer. In: Molecular Therapy. 2011 ; Vol. 19, No. 7. pp. 1254-1262.
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