Journal
MOLECULAR THERAPY
Volume 13, Issue 4, Pages 683-693Publisher
CELL PRESS
DOI: 10.1016/j.ymthe.2005.11.013
Keywords
adeno-associated virus; phage display; endothelium; rat; targeting; systemic delivery
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Funding
- MRC [G0200279] Funding Source: UKRI
- Medical Research Council [G0200279] Funding Source: researchfish
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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 pepticles 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 pepticles 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.
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