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Cell entry targeting restricts biodistribution of replication-competent retroviruses to tumour tissue

Gene Therapy volume 15, pages 1500–1510 (2008)Cite this article

Abstract

Virotherapy is currently being developed for many different types of viruses including replication-competent murine leukaemia virus (MLV) as a novel tool in cancer therapy. However, there is the risk of insertional mutagenesis associated with this virus, making careful preclinical studies necessary before its first application in man. We have previously generated conditionally replication-competent MLV variants that require activation by tumour-associated proteases to become infectious. Here we analysed in a comparative study the spreading of non-targeted and of such tumour-targeted MLV variants to tumour and extratumoural organs in immunodeficient mice. Both virus types were able to efficiently infect tumour cells after systemic administration. The non-targeted virus, however, also infected extratumoural organs like bone marrow, spleen and liver efficiently. In contrast, the targeted viruses revealed in a quantitative analysis of virus spreading an up to 500-fold more selective infection of tumour tissue than the non-targeted virus. The data raise serious doubts about a safe clinical use of non-targeted MLV. Engineering the virus to become activatable by tumour-associated proteases can significantly improve the safety of MLV.

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Acknowledgements

We thank Yuansheng Sun, Cheick Coulibaly and Roland Plesker for supervising animal experimentation, Julia Medvedovska for excellent technical assistance and Christine Hohenadl for critical reading of the paper. This work was supported by grant 107743 of the Deutsche Krebshilfe and grant 01GU0504 of the Bundesministerium für Bildung und Forschung (BMBF) to C.J.B.

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  1. L J Duerner and A Schwantes: These authors contributed equally to this work.

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  1. Abteilung Medizinische Biotechnologie, Paul-Ehrlich-Institut, Langen, Germany

    L J Duerner, A Schwantes, I C Schneider, K Cichutek & C J Buchholz

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  1. L J Duerner
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Correspondence to C J Buchholz.

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

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Duerner, L., Schwantes, A., Schneider, I. et al. Cell entry targeting restricts biodistribution of replication-competent retroviruses to tumour tissue. Gene Ther 15, 1500–1510 (2008). https://doi.org/10.1038/gt.2008.92

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