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Organ distribution of gene expression after intravenous infusion of targeted and untargeted lentiviral vectors

Gene Therapy volume 8, pages 1456–1463 (2001)Cite this article

Abstract

Lentiviral vectors represent an attractive technology platform from which to develop a targetable injectable gene delivery system for transduction of specific cell populations in vivo, irrespective of their cell cycle status. Targeted HIV-1-based lentiviral vectors were generated by pseudotyping them with chimeric murine leukemia virus (MLV) envelope glycoproteins displaying N-terminal targeting polypeptides. Vectors displaying an EGF polypeptide were fully infectious on EGF receptor-negative cells, but were inactive on cells with abundant EGF receptors (inverse targeting). Receptor-mediated inactivation of gene transfer was overcome by competing the EGF receptors on the target cells with soluble EGF or by removing the displayed EGF domain from the surface of the vector particles by factor Xa cleavage of a specific protease substrate engineered into its tethering linker (protease targeting). Intravenous infusion of nontargeted HIV-1 vectors led to maximal luciferase activity in liver and spleen with moderate or minimal activity in heart, skeletal muscle, lung, brain, kidney, ovaries and bone marrow. In contrast, intravenous EGF-displaying vectors were expressed maximally in spleen with very low level luciferase expression detectable in liver (EGF-receptor rich). Liver transduction by the EGF-displaying vector was restored by pretreating the animals with soluble EGF suggesting that these vectors are inversely targeted to spleen. Gene Therapy (2001) 8, 1456–1463.

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Acknowledgements

We thank Dr Tal Kafri for the kind gift of the 293T cells. This work was supported through grants from the Harold W Siebens and George W Eisenberg Foundations and from Cambridge Genetics Ltd, UK.

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Authors and Affiliations

  1. Molecular Medicine Program, Mayo Foundation, Rochester, MN, USA

    K-W Peng, L Pham, H Ye & SJ Russell

  2. Department of Genetics and Microbiology, University of Geneva Medical School, Geneva, Switzerland

    R Zufferey & D Trono

  3. Vectorologie Rétrovirale et Therapie Genique, Unite de Virologie Humaine, Ecole Normale Superieure de Lyon, France

    F-L Cosset

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  1. K-W Peng
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Peng, KW., Pham, L., Ye, H. et al. Organ distribution of gene expression after intravenous infusion of targeted and untargeted lentiviral vectors. Gene Ther 8, 1456–1463 (2001). https://doi.org/10.1038/sj.gt.3301552

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