Adenoviral serotype 5 vectors pseudotyped with fibers from subgroup D show modified tropism in vitro and in vivo

Laura Denby, Lorraine M Work, Delyth Graham, Catherine Hsu, Dan J von Seggern, Stuart A Nicklin, Andrew H Baker

Research output: Contribution to journalArticlepeer-review

Abstract

Adenovirus (Ad5) serotype 5 vectors are commonly used for gene transfer. Preclinical studies have shown that their application to systemic gene delivery, however, is limited by their highly efficient uptake in the liver, principally mediated by receptor-binding sites on the fiber shaft and knob domain. Using Ad to target other sites in vivo requires vectors that lack hepatic tropism. We therefore sought to exploit Ad family diversity to isolate vectors that possessed poor hepatic tropism. We pseudotyped the fibers from Ad16 (subgroup B; Ad5/16), Ad19p (subgroup D; Ad5/19p), and Ad37 (subgroup D; Ad5/37) onto Ad5 capsids and assessed infectivity profiles in vitro in multiple cell types and in vivo in rats. In rat, mouse, and human hepatocytes, Ad5/19p and Ad5/37 both possessed a striking lack of hepatic cell infectivity compared with Ad5. Both vectors were, however, able to transduce human vascular endothelial and smooth muscle cells with efficiencies equal to or greater than that of nonmodified Ad5. We evaluated liver uptake in 12-week-old male rats after intravenous injection. In contrast to a vector with the wild-type Ad5 fiber, Ad5, both Ad5/19p and Ad5/37 produced significantly less virion accumulation (measured at 1 hr and 5 days) and transgene expression in the liver. Thus, Ad5/19p and Ad5/37 may be useful platforms for the development of targeted Ad vectors.

Original languageEnglish
Pages (from-to)1054-64
Number of pages11
JournalHuman Gene Therapy
Volume15
Issue number11
DOIs
Publication statusPublished - Nov 2004

Keywords

  • Adenoviridae
  • Animals
  • Antigens, CD
  • Antigens, CD46
  • Binding Sites
  • Capsid
  • Cell Line
  • Cells, Cultured
  • Coxsackie and Adenovirus Receptor-Like Membrane Protein
  • Endothelial Cells
  • Endothelium, Vascular
  • Gene Transfer Techniques
  • Genetic Vectors
  • Hepatocytes
  • Humans
  • Liver
  • Male
  • Membrane Glycoproteins
  • Mice
  • Mutation
  • Rats
  • Receptors, Virus
  • Reverse Transcriptase Polymerase Chain Reaction
  • Time Factors
  • Transgenes
  • Virion

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