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Combined transductional and transcriptional targeting improves the specificity of transgene expression in vivo

Nature Biotechnology volume 19, pages 838–842 (2001)Cite this article

Abstract

The promise of gene therapy for health care will not be realized until gene delivery systems are capable of achieving efficient, cell-specific gene delivery in vivo. Here we describe an adenoviral system for achieving cell-specific transgene expression in pulmonary endothelium. The combination of transductional targeting to a pulmonary endothelial marker (angiotensin-converting enzyme, ACE) and an endothelial-specific promoter (for vascular endothelial growth factor receptor type 1, flt-1) resulted in a synergistic, 300,000-fold improvement in the selectivity of transgene expression for lung versus the usual site of vector sequestration, the liver. This combined approach should be useful for the design of other gene delivery systems.

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Figure 1: Combined transductional and transcriptional targeting improves the specificity of transgene expression in vivo.
Figure 2: Targeting fidelity is maintained upon left ventricular injection.
Figure 3: Combined targeting shows improved selectivity at high vector dose.
Figure 4: Combined targeting achieves pulmonary-specific transgene expression.
Figure 5: Pulmonary-specific transgene expression is localized to vascular endothelium.

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Acknowledgements

This research was supported by grants from the American Heart Association, NIH-NIDDK P30 DK54781, and the Avon Products Foundation to P.N.R.; NIH-NCI RO1 CA74242 to D.T.C. and British Heart Foundation (PG97/018 and PG99/097) grants to A.H.B. We would also like to thank Masato Yamamoto for providing the AdCMVLuc virus, and Long Le, Kathee Mercer, and the UAB Image Analysis Core for technical assistance.

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Authors and Affiliations

  1. Division of Human Gene Therapy, Departments of Medicine, Surgery and Pathology, and Gene Therapy Center, University of Alabama at Birmingham, Birmingham, AL, USA

    Paul N. Reynolds, Lioudmila Kaliberova, Brian G. Boatman, William E. Grizzle & David T. Curiel

  2. Department of Medicine and Therapeutics, University of Glasgow, Glasgow, UK

    Stuart A. Nicklin & Andrew H. Baker

  3. Division of Cardiology, University of Alabama at Birmingham, Birmingham, AL, USA

    Brian G. Boatman

  4. Department of Anesthesiology, University of Illinois at Chicago, Chicago, IL, USA

    Irina V. Balyasnikova & Sergei M. Danilov

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Correspondence to Paul N. Reynolds.

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Reynolds, P., Nicklin, S., Kaliberova, L. et al. Combined transductional and transcriptional targeting improves the specificity of transgene expression in vivo. Nat Biotechnol 19, 838–842 (2001). https://doi.org/10.1038/nbt0901-838

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