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PET imaging of thymidine kinase gene expression in the liver of non-human primates following systemic delivery of an adenoviral vector

Gene Therapy volume 16, pages 136–141 (2009)Cite this article

Abstract

Non-invasive in vivo imaging of transgene expression is currently providing very important means to optimize gene therapy regimes. Results in non-human primates are considered the most predictive models for the outcome in patients. In this study, we have documented that tumour and primary cell lines from human and non-human primates are comparably gene-transduced in vitro by serotype 5 adenovirus expressing HSV1-thymidine kinase. Transgene expression can be quantified in human and monkey cultured cells by positron emission tomography (PET) imaging when transduced cells are incubated with a fluoride-18 labelled penciclovir analogue. In our hands, PET images of cell cultures estimate the number of transduced cells rather than intensity of transgene expression once a threshold of TK per cell is reached. Interestingly, in vivo systemic administration of a clinical grade recombinant adenovirus expressing TK into macaques gives rise to an intense retention of the radiotracer in the liver parenchyma, providing an experimental system to visualize transgene expression that ought to be similar in human and macaques. Such imaging methodology might contribute to improve strategies based on adenoviral vectors.

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Acknowledgements

This work was supported, in part, by grants from UTE project of Centro de Investigación Médica Aplicada, University of Navarra, EU VII Framework program (ENCITE), MEC (SAF2005-03131), Fondo de Investigación Sanitaria (PI061475 and PI060932), Departamento de Educación del Gobierno de Navarra, Departamento de Salud del Gobierno de Navarra (Beca Ortiz de Landázuri). Redes Temáticas de Investigación Cooperativa RETIC (RD06/0020/0065), Fundación Mutua Madrileña. We are grateful to Izaskun Bilbao and Margarita Ecay for MicroPET analysis as well as Elena Ciordia and Javier Guillén for animal care and vivarium management. Rubén Hernández-Alcoceba and Juan Dubrot are acknowledged for scientific discussion and support.

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Author notes

  1. I Melero and I Peñuelas: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Gene Therapy and Hepatology, Centre for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain

    A Fontanellas, S Hervas-Stubbs, A Sampedro, A Azpilicueta, I Mauleón, A Pañeda, J Prieto & I Melero

  2. MicroPET Research Unit, CIMA–CUN, University of Navarra, Pamplona, Spain

    M Collantes & I Peñuelas

  3. Department of Nuclear Medicine, Clínica Universitaria, University of Navarra, Pamplona, Spain

    G Quincoces & I Peñuelas

  4. CIBER en enfermedades hepáticas y digestivas, Spain

    J Prieto

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  1. A Fontanellas
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  11. I Peñuelas
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Correspondence to I Melero.

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Supplementary Information accompanies the paper on Gene Therapy website (http://www.nature.com/gt)

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Fontanellas, A., Hervas-Stubbs, S., Sampedro, A. et al. PET imaging of thymidine kinase gene expression in the liver of non-human primates following systemic delivery of an adenoviral vector. Gene Ther 16, 136–141 (2009). https://doi.org/10.1038/gt.2008.122

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