Biodistribution and retargeting of FX-binding ablated adenovirus serotype 5 vectors

Raul Alba, Angela C Bradshaw, Lynda Coughlan, Laura Denby, Robert A McDonald, Simon N Waddington, Suzanne M K Buckley, Jenny A Greig, Alan L Parker, Ashley M Miller, Hongjie Wang, Andre Lieber, Nico van Rooijen, John H McVey, Stuart A Nicklin, Andrew H Baker

Research output: Contribution to journalArticlepeer-review

Abstract

A major limitation for adenoviral transduction in vivo is the profound liver tropism of adenovirus type 5 (Ad5). Recently, we demonstrated that coagulation factor X (FX) binds to Ad5-hexon protein at high affinity to mediate hepatocyte transduction after intravascular delivery. We developed novel genetically FX-binding ablated Ad5 vectors with lower liver transduction. Here, we demonstrate that FX-binding ablated Ad5 predominantly localize to the liver and spleen 1 hour after injection; however, they had highly reduced liver transduction in both control and macrophage-depleted mice compared with Ad5. At high doses in macrophage-depleted mice, FX-binding ablated vectors transduced the spleen more efficiently than Ad5. Immunohistochemical studies demonstrated transgene colocalization with CD11c(+), ER-TR7(+), and MAdCAM-1(+) cells in the splenic marginal zone. Systemic inflammatory profiles were broadly similar between FX-binding ablated Ad5 and Ad5 at low and intermediate doses, although higher levels of several inflammatory proteins were observed at the highest dose of FX-binding ablated Ad5. Subsequently, we generated a FX-binding ablated virus containing a high affinity Ad35 fiber that mediated a significant improvement in lung/liver ratio in macrophage-depleted CD46(+) mice compared with controls. Therefore, this study documents the biodistribution and reports the retargeting capacity of FX binding-ablated Ad5 vectors in vitro and in vivo.

Original languageEnglish
Pages (from-to)2656-64
Number of pages9
JournalBlood
Volume116
Issue number15
DOIs
Publication statusPublished - 14 Oct 2010

Keywords

  • Adenoviruses, Human
  • Animals
  • Capsid Proteins
  • Chemokines
  • Cytokines
  • Factor X
  • Genetic Vectors
  • Humans
  • Inflammation Mediators
  • Liver
  • Lung
  • Male
  • Mice
  • Mice, Transgenic
  • Protein Binding
  • Recombinant Proteins
  • Serotyping
  • Spleen
  • Time Factors
  • Tissue Distribution
  • Transduction, Genetic
  • beta-Galactosidase

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