Abstract
Lentiviruses have shown great promise for human gene therapy. However, no optimal strategies are yet available for noninvasive imaging of virus biodistribution and subsequent transduction in vivo. We have developed a dual-imaging strategy based on avidin–biotin system allowing easy exchange of the surface ligand on HIV-derived lentivirus envelope. This was achieved by displaying avidin or streptavidin fused to the transmembrane anchor of vesicular stomatitis virus G protein on gp64-pseudotyped envelopes. Avidin and streptavidin were efficiently incorporated on virus particles, which consequently showed binding to biotin in ELISA. These vectors, conjugated to biotinylated radionuclides and engineered to express a ferritin transgene, enabled for the first-time dual imaging of virus biodistribution and transduction pattern by single-photon emission computed tomography and magnetic resonance imaging after stereotactic injection into rat brain. In addition, vector retargeting to cancer cells overexpressing CD46, epidermal growth factor and transferrin receptors using biotinylated ligands and antibodies was demonstrated in vitro. In conclusion, we have generated novel lentivirus vectors for noninvasive imaging and targeting of lentivirus-mediated gene delivery. This study suggests that these novel vectors could be applicable for the treatment of central nervous system disorders and cancer.
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Acknowledgements
We thank Siiri Väistö, Juha Ruuskanen, Anne Martikainen, Katja Salminen, Joonas Malinen and Riikka Eisto for excellent technical assistance. We thank Ann-Marie Määttä and Haritha Samaranayake for their help with the animal work. We are grateful to Olli Laitinen for fruitful conversations during the course of the project. We thank Markku Kulomaa for providing streptavidin-encoding plasmid and anti-avidin antibody and Edward A Bayer and Meir Wilchek for the generous gift of anti-streptavidin. We also thank Paolo Arosio for the rHO2 antibody. This study was supported by Ark Therapeutics Group Plc., Finnish Academy, Finnish Foundation for Cardiovascular Research and Finnish Cultural Foundation, North Savo Regional fund.
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Kaikkonen, M., Lesch, H., Pikkarainen, J. et al. (Strept)avidin-displaying lentiviruses as versatile tools for targeting and dual imaging of gene delivery. Gene Ther 16, 894–904 (2009). https://doi.org/10.1038/gt.2009.47
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DOI: https://doi.org/10.1038/gt.2009.47
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