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Generation of optimized and urokinase-targeted oncolytic Sendai virus vectors applicable for various human malignancies

Gene Therapy volume 16, pages 392–403 (2009)Cite this article

Abstract

We previously reported the development of a prototype ‘oncolytic Sendai virus (SeV) vector’ formed by introducing two major genomic modifications to the original SeV, namely deletion of the matrix (M) gene to avoid budding of secondary viral particles and manipulation of the trypsin-dependent cleavage site of the fusion (F) gene to generate protease-specific sequences. As a result, the ‘oncolytic SeV’ that was susceptible to matrix metalloproteinases (MMPs) was shown to selectively kill MMP-expressing tumors through syncytium formation in vitro and in vivo. However, its efficacy has been relatively limited because of the requirement of higher expression of MMPs and smaller populations of MMP-expressing tumors. To overcome these limitations, we have designed an optimized and dramatically powerful oncolytic SeV vector. Truncation of 14-amino acid residues of the cytoplasmic domain of F protein resulted in dramatic enhancement of cell-killing activities of oncolytic SeV, and the combination with replacement of the trypsin cleavage site with the new urokinase type plasminogen activator (uPA)-sensitive sequence (SGRS) led a variety of human tumors, including prostate (PC-3), renal (CAKI-I), pancreatic (BxPC3) and lung (PC14) cancers, to extensive death through massive cell-to-cell spreading without significant dissemination to the surrounding noncancerous tissue in vivo. These results indicate a dramatic improvement of antitumor activity; therefore, extensive utility of the newly designed uPA-targeted oncolytic SeV has significant potential for treating patients bearing urokinase-expressing cancers in clinical settings.

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Acknowledgements

This work was supported in part by Research Grants from the 21st Century Center of Excellence Program, Chiba University Graduate School of Medicine, and by Grants-in-Aid (to YY) from the Japanese Ministry of Education, Culture, Sports, Science and Technology. We thank B Moss, D Kolakofsky, I Saito and H Iba for supplying experimental materials essential for this study; K Ishida, T Kanaya, T Yamamoto, M Yoshizaki, A Tagawa, E Suzuki and N Kohno for their excellent technical assistance; and T Hironaka, T Zhu and A Iida for helpful discussions.

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Authors and Affiliations

  1. Department of Gene Therapy, Chiba University Graduate School of Medicine, Chiba, Japan

    H Kinoh, A Komaru, Y Ueda & Y Yonemitsu

  2. DNAVEC Corporation, Tsukuba, Ibaraki, Japan

    M Inoue & M Hasegawa

  3. Department of Urology, Chiba University Graduate School of Medicine, Chiba, Japan

    A Komaru

Authors
  1. H Kinoh
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  2. M Inoue
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  3. A Komaru
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  4. Y Ueda
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  5. M Hasegawa
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  6. Y Yonemitsu
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Correspondence to H Kinoh.

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

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Kinoh, H., Inoue, M., Komaru, A. et al. Generation of optimized and urokinase-targeted oncolytic Sendai virus vectors applicable for various human malignancies. Gene Ther 16, 392–403 (2009). https://doi.org/10.1038/gt.2008.167

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