Edinburgh Research Explorer

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

Research output: Contribution to journalArticle

  • 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

Related Edinburgh Organisations

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

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.

    Research areas

  • 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

ID: 23490202