Vascular bed-targeted in vivo gene delivery using tropism-modified adeno-associated viruses

Work, L.M. et al. (2006) Vascular bed-targeted in vivo gene delivery using tropism-modified adeno-associated viruses. Molecular Therapy, 13(4), pp. 683-693. (doi:10.1016/j.ymthe.2005.11.013)

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Abstract

Virus-mediated gene delivery is restricted by the infectivity profile of the chosen vector. Targeting the vascular endothelium via systemic delivery has been attempted using peptides isolated in vitro (using either phage or vector display) and implicit reliance on target receptor expression in vivo. This has limited application since endothelial cells in vitro and in vivo differ vastly in receptor profiles and because of the existence of complex endothelial "zip codes" in vivo. We therefore tested whether in vivo phage display combined with adeno-associated virus (AAV) capsid modifications would allow in vivo homing to the endothelium residing in defined organs. Extensive in vivo biopanning in rats identified four consensus peptides homing to the lung or brain. Each was incorporated into the VP3 region of the AAV-2 capsid to display the peptide at the virion surface. Peptides that conferred heparan independence were shown to retarget virus to the expected vascular bed in vivo in a preferential manner, determined 28 days post-systemic injection by both virion DNA and transgene expression profiling. Our findings significantly impact the design of viral vectors for targeting individual vascular beds in vivo.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Nicklin, Professor Stuart and Baker, Professor Andrew and Denby, Dr Laura and Work, Dr Lorraine and Britton, Ms Nicola
Authors: Work, L.M., Buning, H., Hunt, E., Nicklin, S.A., Denby, L., Britton, N., Leike, K., Odenthal, M., Drebber, U., Hallek, M., and Baker, A.H.
College/School:College of Medical Veterinary and Life Sciences
College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:Molecular Therapy
Publisher:Nature Publishing Group
ISSN:1525-0016
ISSN (Online):1525-0024
Published Online:01 January 2006

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
329371Development and evaluation of novel adeno-associated viral vectors for long term gene therapyAndrew BakerMedical Research Council (MRC)G0200279Institute of Cardiovascular and Medical Sciences