title: Targeted gene delivery to vascular tissue in vivo by tropism-modified adeno-associated virus vectors.
abstract: BACKGROUND
  Gene therapy offers an unprecedented opportunity to treat diverse pathologies. Adeno-associated virus (AAV) is a promising gene delivery vector for cardiovascular disease. However, AAV transduces the liver after systemic administration, reducing its usefulness for therapies targeted at other sites. Because vascular endothelial cells (ECs) are in contact with the bloodstream and are heterogeneous between organs, they represent an ideal target for site-specific delivery of biological agents.
  
  
  RESULTS
  We isolated human venous EC-targeting peptides by phage display and genetically incorporated them into AAV capsids after amino acid 587. Peptide-modified AAVs transduced venous (but not arterial) ECs in vitro, whereas hepatocyte transduction was significantly lower than with native AAV. Intravenous infusion of engineered AAVs into mice produced reduced vector accumulation in liver measured 1 hour and 28 days after injection and delayed blood clearance rates compared with native AAV. Peptide-modified AAVs produced enhanced uptake of virions in the vena cava with selective transgene expression. Retargeting was dose dependent, and coinfusion of either heparin or free competing peptides indicated that uptake was principally independent of native AAV tropism and mediated via the peptide.
  
  
  CONCLUSIONS
  AAV tropism can be genetically engineered by use of phage display-derived peptides to generate vectors that are selective for the vasculature.
authors.affiliation: Bristol Heart Institute, Bristol Royal Infirmary, Bristol, UK.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: White
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Nicklin
authors.forename: Hildegard
authors.initials: H
authors.lastname: Büning
authors.forename: M Julia
authors.initials: MJ
authors.lastname: Brosnan
authors.forename: Kristen
authors.initials: K
authors.lastname: Leike
authors.forename: Emmanuel D
authors.initials: ED
authors.lastname: Papadakis
authors.forename: Michael
authors.initials: M
authors.lastname: Hallek
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Baker
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D000229:Dependovirus / Q000235:genetics*; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D005818:Genetic Engineering; D005822:Genetic Vectors / Q000493:pharmacokinetics*; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D019151:Peptide Library; D010455:Peptides / Q000235:genetics; D014161:Transduction, Genetic
chemical_list: D019151:Peptide Library; D010455:Peptides