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Enhanced therapeutic efficacy of G207 for the treatment of glioma through Musashi1 promoter retargeting of γ34.5-mediated virulence

Gene Therapy volume 13, pages 106–116 (2006)Cite this article

Abstract

G207 is a conditionally replicating derivative of herpes simplex virus type1 (HSV-1) engineered with deletions of both ICP34.5 loci and a lacZ insertion disabling the ICP6 gene. G207 exhibits an efficient oncolytic activity in vitro and in vivo, yet minimal toxicity in normal tissue, and is now in clinical trial for malignant glioma. According to the results of clinical trials, however, although G207 was proved to be safe, the efficacy was not so impressive. Deletion of the ICP34.5 gene coding for virulence made G207 extremely safe, but it markedly reduced the cytotoxicity mediated by HSV-1. To enhance the therapeutic efficacy of G207 without diminishing its safety, we used a defective vector containing Musashi1 promoter/ICP34.5, with G207 as helper virus. P/musashi1 was functional selectively in human glioma cell lines (U87MG, U251, T98G) in this study and dvM345 showed a much higher therapeutic efficacy both in culture and in the in vivo glioma model, than G207 alone, without diminishing its favorable toxicity profile. These results suggest that transcriptional regulation of ICP34.5 by P/musashi1 can be used to target HSV-1 virulence toward gliomas while maintaining the desirable neuroattenuated phenotype.

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Acknowledgements

We thank Drs Robert L Martuza and Samuel D Rabkin for their valuable scientific support. We are also indebted to Dr Takashi Ohigashi, Yoshihide Otani, and the entire staff of the Department of Neurosurgery, School of Medicine, Keio University for their technical assistance. This work was supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology, Japan to TY, a Grant-in-Aid for Scientific Research from Japan Society for Promotion of Science, and Keio Gijuku Academic Development Funds to TY.

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Authors and Affiliations

  1. Molecular Neurosurgery Laboratory, School of Medicine, Keio University, Tokyo, Japan

    R Kanai, H Tomita, A Shinoda, M Takahashi & T Yazaki

  2. Department of Neurosurgery, School of Medicine, Keio University, Tokyo, Japan

    R Kanai, H Tomita, T Kawase & T Yazaki

  3. Department of Neurosurgery, Chiba Neurosurgical Hospital, Chiba, Japan

    A Shinoda

  4. Department of Physiology, School of Medicine, Keio University, Tokyo, Japan

    M Takahashi & H Okano

  5. Department of Neurology, University of Rochester Medical Center, Rochester, NY 14642, USA

    S Goldman

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Kanai, R., Tomita, H., Shinoda, A. et al. Enhanced therapeutic efficacy of G207 for the treatment of glioma through Musashi1 promoter retargeting of γ34.5-mediated virulence. Gene Ther 13, 106–116 (2006). https://doi.org/10.1038/sj.gt.3302636

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