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(Circulation. 2004;109:513-519.)
© 2004 American Heart Association, Inc.

Basic Science Reports

Targeted Gene Delivery to Vascular Tissue In Vivo by Tropism-Modified Adeno-Associated Virus Vectors

Stephen J. White, DPhil^*; Stuart A. Nicklin, PhD^*; Hildegard Büning, PhD; M. Julia Brosnan, PhD; Kristen Leike; Emmanuel D. Papadakis, BSc; Michael Hallek, MD; Andrew H. Baker, PhD

From the Bristol Heart Institute, Bristol Royal Infirmary, Bristol (S.J.W., E.D.P.), and the Division of Cardiovascular and Medical Sciences, University of Glasgow (S.A.N., M.J.B., A.H.B.), UK; and the Laboratorium für Molekulare Biologie, Genzentrum, Ludwig-Maximilians Universität München (H.B., K.L., M.H.), the Medizinische Klinik III, Klinikum der Universität München (M.H.), and Gesellshaft für Strahelforschung (M.H.), Munich, Germany.

Correspondence to Dr A.H. Baker, Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, G11 6NT UK. E-mail ab11f{at}clinmed.gla.ac.uk

Received May 9, 2003; de novo received August 12, 2003; revision received September 23, 2003; accepted September 25, 2003.

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.

Methods and 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.

Key Words: gene therapy • endothelium • viruses • peptides

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