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Lentiviral vector retargeting to P-glycoprotein on metastatic melanoma through intravenous injection

Nature Medicine volume 11, pages 346–352 (2005)Cite this article

Abstract

Targeted gene transduction to specific tissues and organs through intravenous injection would be the ultimate preferred method of gene delivery. Here, we report successful targeting in a living animal through intravenous injection of a lentiviral vector pseudotyped with a modified chimeric Sindbis virus envelope (termed m168). m168 pseudotypes have high titer and high targeting specificity and, unlike other retroviral pseudotypes, have low nonspecific infectivity in liver and spleen. A mouse cancer model of metastatic melanoma was used to test intravenous targeting with m168. Human P-glycoprotein was ectopically expressed on the surface of melanoma cells and targeted by the m168 pseudotyped lentiviral vector conjugated with antibody specific for P-glycoprotein. m168 pseudotypes successfully targeted metastatic melanoma cells growing in the lung after systemic administration by tail vein injection. Further development of this targeting technology should result in applications not only for cancers but also for genetic, infectious and immune diseases.

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Figure 1: HIV vector pseudotyped by ZZ SINDBIS has nonspecific infectivity in the absence of target-specific antibody in vitro and in vivo.
Figure 2: Generation of ZZ SINDBIS mutants to reduce nonspecific infection.
Figure 3: The m168 pseudotyped lentiviral vector has reduced nonspecific infectivity and mediates antibody-directed targeted gene transduction after systemic injection into mice.

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Acknowledgements

We thank E.S. Withers-Ward and L. Lowe for manuscript preparation, S. Gambhir and D. Stout for supporting in vivo imaging, S. Cole and M. Sato for technical assistance with real time PCR, D. Baltimore, W. Osborne, B. Sorrentino, P. Charneau and M. Miyasaka for providing reagents, and V. Hearing, S. Leong and T. Miyamoto for assistance with histological analysis. This work was supported by US National Institutes of Health grants CA-92194, AI039975, AI028697 (UCLA CFAR).

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Authors and Affiliations

  1. Department of Microbiology, Immunology and Molecular Genetics, University of California, 10833 Le Conte Avenue, Los Angeles, 90095, California, USA

    Kouki Morizono, Yiming Xie, Gene-Errol Ringpis, Hoorig Nassanian, Benhur Lee & Irvin S Y Chen

  2. UCLA AIDS Institute, University of California, 10833 Le Conte Avenue, Los Angeles, 90095, California, USA

    Kouki Morizono, Yiming Xie, Gene-Errol Ringpis & Irvin S Y Chen

  3. Department of Urology, University of California, 10833 Le Conte Avenue, Los Angeles, 90095, California, USA

    Mai Johnson & Lily Wu

  4. Department of Pathology and Laboratory Medicine, University of California, 10833 Le Conte Avenue, Los Angeles, 90095, California, USA

    Benhur Lee

  5. Department of Medicine, David Geffen School of Medicine, University of California, 10833 Le Conte Avenue, Los Angeles, 90095, California, USA

    Irvin S Y Chen

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  1. Kouki Morizono
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Correspondence to Irvin S Y Chen.

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Supplementary information

Supplementary Fig. 1

Schematic representation of FUhLucW, FUIntronRW and CCRMDRsc1 (PDF 606 kb)

Supplementary Fig. 2

Anti-SINDBIS virus antibody blocked non-specific background infectivity of the ZZ SINDBIS pseudotyped lentiviral vector. (PDF 762 kb)

Supplementary Fig. 3

The m168 pseudotyped lentiviral vector demonstrates a higher specificity of infection in melanoma cell in vitro. (PDF 741 kb)

Supplementary Fig. 4

Expression of human P-glycoprotein on the surface of cells isolated from metastatic tumors used in the in vitro luciferase and PCR assay. (PDF 676 kb)

Supplementary Fig. 5

Immunohistochemical analysis of metastasized tumors targeted by FUGW (m168) with anti-P-glycoprotein. (PDF 981 kb)

Supplementary Fig. 6

Analysis of gene transduction in liver and spleen. (PDF 816 kb)

Supplementary Table 1

Analysis of properties of mutants (PDF 34 kb)

Supplementary Methods (PDF 54 kb)

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Morizono, K., Xie, Y., Ringpis, GE. et al. Lentiviral vector retargeting to P-glycoprotein on metastatic melanoma through intravenous injection. Nat Med 11, 346–352 (2005). https://doi.org/10.1038/nm1192

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