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Treatment of multifocal breast cancer by systemic delivery of dual-targeted adeno-associated viral vectors

Gene Therapy volume 22, pages 840–847 (2015)Cite this article

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A Corrigendum to this article was published on 08 October 2015

This article has been updated

Abstract

Adeno-associated viral (AAV) vectors yield high potential for clinical gene therapy but, like for other vectors systems, they frequently do not sufficiently transduce the target tissue and their unspecific tropism prevents their application for multifocal diseases such as disseminated cancer. Targeted AAV vectors have been obtained from random AAV display peptide libraries but so far, all vector variants selected from AAV libraries upon systemic administration in vivo retained some collateral tropism, frequently the heart. Here we explored, if this impediment can be overcome by microRNA-regulated transgene cassettes as the combination of library-derived capsid targeting and micro-RNA control has not been evaluated so far. We used a tumor-targeted AAV capsid variant (ESGLSQS) selected from random AAV-display peptide libraries in vivo with remaining off-target tropism toward the heart and regulated targeted transgene expression in vivo by complementary target elements for heart-specific microRNA (miRT-1d). Although this vector still maintained its strong transduction capacity for tumor target tissue after intravenous injection, transgene expression in the heart was almost completely abrogated. This strong and completely tumor-specific transgene expression was used for therapeutic gene transfer in an aggressive multifocal, transgenic, polyoma middle T-induced, murine breast cancer model. A therapeutic suicide gene, delivered systemically by this dual-targeted AAV vector to multifocal breast cancer, significantly inhibited tumor growth after one single vector administration while avoiding side effects compared with untargeted vectors.

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  • 08 October 2015

    This article has been corrected since Advance Online Publication and a corrigendum is also printed in this issue

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Acknowledgements

We thank Dr Tomas Streichert, Department of clinical chemistry and the Core Facility for OIVI at the University Medical Center Hamburg Eppendorf for technical support and we thank the animal facility of the University Medical Center Hamburg-Eppendorf for excellent animal care. This work was supported by the German Research Foundation (DFG, grant numbers TR448/5-3 to MT, Mu1654/3-2 to JAK and 516/8-2 to JAK), the Deutsche Krebshilfe (grant number 110902 to MT) and the Margarethe Clemens Foundation (endowed professorship to MT).

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Author notes

  1. M Trepel and J Körbelin: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Oncology and Hematology, Hubertus Wald Cancer Center, University Medical Center Hamburg-Eppendorf, Martinistr, Hamburg, Germany

    M Trepel, J Körbelin, E Spies, A Hunger & S Michelfelder

  2. Department of Hematology and Oncology, Augsburg Medical Center, Stenglinstr, Augsburg, Germany

    M Trepel

  3. University Hospital Heidelberg, Heidelberg, and DZHK (German Center for Cardiovascular Research), partner site Heidelberg/Mannheim, Im Neuenheimer Feld 410, Heidelberg, Germany

    M B Heckmann, H A Katus & O J Müller

  4. Department of Cell and Gene Therapy, Bone Marrow Transplantation Unit Research, University Medical Center Hamburg-Eppendorf, Martinistr, Hamburg, Germany

    B Fehse

  5. Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 242, Heidelberg, Germany

    J A Kleinschmidt

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  1. M Trepel
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Correspondence to M Trepel.

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Trepel, M., Körbelin, J., Spies, E. et al. Treatment of multifocal breast cancer by systemic delivery of dual-targeted adeno-associated viral vectors. Gene Ther 22, 840–847 (2015). https://doi.org/10.1038/gt.2015.52

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