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A novel system for mitigation of ectopic transgene expression induced by adenoviral vectors

Gene Therapy volume 8, pages 1271–1275 (2001)Cite this article

Abstract

Adenoviral (Ad) vectors are good candidates for gene therapy in view of their high in vivo gene delivery efficiency. However, greater control over the tissue distribution of transgene expression is required to avoid potentially deleterious effects in non-target organs. In this regard, the liver is particularly at risk due to the high natural tropism of Ad for this organ, where dose limiting toxicity has been seen due to toxic transgene expression. We hypothesized that the cre/loxP system could be utilized to reduce unintended transgene expression at this site. This concept was tested using an Ad vector (AdLCLLL) carrying a reporter gene cassette in which the promoter and luciferase gene were flanked by LoxP sequences. Co-administration of this vector with a second vector carrying the cre recombinase gene in vitro and in vivo resulted in specific down-regulation of transgene expression. This novel approach thus has the potential to improve the safety of gene therapy strategies that rely upon the delivery of genes which may be hepatotoxic.

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Acknowledgements

This work was supported by the following grants: NIH R01 CA74242, NIH R01 HL50255, NIH R01 CA 86881–01 and NCI N01C0–97110.

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Authors and Affiliations

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

    PN Reynolds, Y Adachi, L Kaliberova & DT Curiel

  2. Thoracic Medicine Department, Royal Adelaide Hospital, Adelaide, South Australia, Australia

    MD Holmes

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  1. PN Reynolds
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  2. MD Holmes
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  3. Y Adachi
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  4. L Kaliberova
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Reynolds, P., Holmes, M., Adachi, Y. et al. A novel system for mitigation of ectopic transgene expression induced by adenoviral vectors. Gene Ther 8, 1271–1275 (2001). https://doi.org/10.1038/sj.gt.3301511

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