A myeloid cell-binding adenovirus efficiently targets gene transfer to the lung and escapes liver tropism

M. O. Alberti, J. S. Deshane, D. D. Chaplin, L. Pereboeva, D. T. Curiel, J. C. Roth

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

Specific and efficient gene delivery to the lung has been hampered by liver sequestration of adenovirus serotype 5 (Ad5) vectors. The complexity of Ad5 liver tropism has largely been unraveled, permitting improved efficacy of Ad5 gene delivery. However, Kupffer cell (KC) scavenging and elimination of Ad5 still represent major obstacles to lung gene delivery strategies. KC uptake substantially reduces bioavailability of Ad5 for target tissues and compensatory dose escalation leads to acute hepatotoxicity and a potent innate immune response. Here, we report a novel lung-targeting strategy through redirection of Ad5 binding to the concentrated leukocyte pool within the pulmonary microvasculature. We demonstrate that this leukocyte-binding approach retargets Ad5 specifically to lung endothelial cells and prevents KC uptake and hepatocyte transduction, resulting in 165 000-fold enhanced lung targeting, compared with Ad5. In addition, myeloid cell-specific binding is preserved in single-cell lung suspensions and only Ad.MBP-coated myeloid cells achieved efficient endothelial cell transduction ex vivo. These findings demonstrate that KC sequestration of Ad5 can be prevented through more efficient uptake of virions in target tissues and suggest that endothelial transduction is achieved by leukocyte-mediated 'hand-off' of Ad.

Original languageEnglish
Pages (from-to)733-741
Number of pages9
JournalGene therapy
Volume20
Issue number7
DOIs
StatePublished - Jul 2013

Keywords

  • Adenovirus
  • Endothelial cell
  • Myeloid
  • Pulmonary
  • Targeting
  • Vasculature

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