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Sstr2A: a relevant target for the delivery of genes into human glioblastoma cells using fiber-modified adenoviral vectors

Gene Therapy volume 20, pages 283–297 (2013)Cite this article

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Abstract

Glioblastomas are the most aggressive of the brain tumors occurring in adults and children. Currently available chemotherapy prolongs the median survival time of patients by only 4 months. The low efficiency of current treatments is partly owing to the blood–brain barrier, which restricts the penetration of most drugs into the central nervous system. Locoregional treatment strategies thus become mandatory. In this context, viral tools are of great interest for the selective delivery of genes into tumoral cells. Gliomas express high levels of type 2 somatostatin receptors (sstr2A), pinpointing them as suitable targets for the improvement of transduction efficiency in these tumors. We designed a new adenoviral vector based on the introduction of the full-length somatostatin (SRIF (somatotropin release-inhibiting factor)) sequence into the HI loop of the HAdV fiber protein. We demonstrate that (i) HAdV-5-SRIF uptake into cells is mediated by sstr2A, (ii) our vector drives high levels of gene expression in cells expressing endogenous sstr2A, with up to 65-fold enhancement and (iii) low doses of HAdV-5-SRIF are sufficient to infect high-grade human primary glioblastoma cells. Adenoviral vectors targeting SRIF receptors might thus represent a promising therapeutic approach to brain tumors.

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Acknowledgements

This work was supported by the Inserm, CNRS, IMPRT, University of Lille 2, Région Nord/Pas-de-Calais, FEDER, DN2M and grants from ANR-08-MNPS-002/AMYTOXTAU and the European Community: MEMOSAD (FP7 contract 200611), FRC (‘Fondation pour la Recherche sur le Cerveau’), Ligue Nationale contre le Cancer (Comité du Nord), Institut de Recherches sur le Cancer de Lille, IRCL. Dr Dournaud was supported by the Université Denis Diderot-Paris 7, Assistance Publique-Hôpitaux de Paris (AP-HP) (contrat d’interface), Association pour la Recherche sur le Cancer (ARC) and FRC. The authors are grateful to Dr Galas, Dr Blum and Dr Caillet-Boudin for their thoughtful discussion and critical reading of the manuscript. We are also grateful to the IMPRT (Institut de Médecine Prédictive et de Recherche Thérapeutique, Lille) for access to core facilities (electron microscopy, cell sorting and confocal microscopy).

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  1. K Lécolle and S Bégard: These two authors contributed equally to this work.

Authors and Affiliations

  1. Inserm, UMR837, rue Polonovski, Lille, France

    K Lécolle, S Bégard, R Caillierez, D Demeyer, E Grellier, A Loyens, J C Beauvillain, J C D'Halluin, M Baroncini, A Sharif, V Prévot, L Buée & M Colin

  2. University Lille Nord de France, UDSL, Faculté de Médecine, IMPRT, JPARC, Place de Verdun, Lille, France

    K Lécolle, S Bégard, R Caillierez, D Demeyer, E Grellier, A Loyens, J C Beauvillain, M Baroncini, J P Lejeune, A Sharif, V Prévot, L Buée & M Colin

  3. Inserm, Unité mixte de recherché UMR676, Université de Médecine Denis Diderot-Paris 7, Paris, France

    Z Csaba & P Dournaud

  4. CHU-Lille, Lille, France

    M Baroncini, J P Lejeune, V Prévot & L Buée

  5. Team of neurosurgery of CHRU of Lille, CHRU, Lille, France

    M Baroncini & J P Lejeune

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  1. K Lécolle
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Lécolle, K., Bégard, S., Caillierez, R. et al. Sstr2A: a relevant target for the delivery of genes into human glioblastoma cells using fiber-modified adenoviral vectors. Gene Ther 20, 283–297 (2013). https://doi.org/10.1038/gt.2012.39

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