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Impact of deletion of envelope-related genes of recombinant Sendai viruses on immune responses following pulmonary gene transfer of neonatal mice

Gene Therapy volume 14, pages 1017–1028 (2007)Cite this article

Abstract

We demonstrated previously that the additive-type recombinant Sendai virus (rSeV) is highly efficient for use in pulmonary gene transfer; however, rSeV exhibits inflammatory responses. To overcome this problem, we tested newly developed non-transmissible constructs, namely, temperature-sensitive F-deleted vector, rSeV/dF (ts-rSeV/dF) and a rSeV with all the envelope-related genes deleted (rSeV/dFdMdHN), for pulmonary gene transfer in neonatal mice, by assessing their toxicity and immune responses. The gene expression in the lungs of neonatal ICR mice peaked on day 2, then gradually decreased until almost disappearing at 14 days after infection in all constructs. Loss of body weight and mortality rate, however, were dramatically improved in mice treated with SeV/dFdMdHN (mortality=0%, n=41) and ts-rSeV/dF (24.2%, n=33) compared with additive rSeV (70.7%, n=58). Although the deletion of envelope-related genes of SeV had a small impact on the production of antibody and cytotoxic T-lymphocyte activity in both adults and neonates, a dramatic reduction was found in the events related to innate responses, including the production of proinflammatory cytokines, particularly in the case of neonates. These results indicate that pulmonary gene transfer using SeV/dFdMdHN warrants further investigation for its possible use in developing safer therapeutics for neonatal lung diseases, including cystic fibrosis.

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Acknowledgements

We thank Drs Mariko Yoshizaki, Akihiro Tagawa, Takumi Kanaya, Hiroshi Ban, and Takashi Hironaka for their excellent technical assistance with the construction and large-scale production of rSeV vectors, and to Ms Chie Arimatsu for her invaluable help with the animal experiments. This work was supported in part by a grant-in-aid (to YY and KS) from the Japanese Ministry of Education, Culture, Sports, Science, and Technology, and Research Grants from the Sankyo Foundation of Life Science (to YY), Mitsubishi Pharma Research Foundation (to YY), and Uehara Memorial Foundation (to YY).

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  1. Y Yonemitsu

    Present address: 4Present address: Department of Gene Therapy at the 21st Century COE Program, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba, Japan.,

Authors and Affiliations

  1. Division of Pathophysiological and Experimental Pathology, Department of Pathology, Kyushu University, Fukuoka, Japan

    S Tanaka, Y Yonemitsu, K Yoshida, S Okano, H Kondo & K Sueishi

  2. Department of Pediatric Surgery, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

    S Tanaka, K Masumoto, S Suita & T Taguchi

  3. DNAVEC Corporation, Tsukuba, Ibaraki, Japan

    M Inoue & M Hasegawa

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  1. S Tanaka
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Correspondence to Y Yonemitsu.

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Tanaka, S., Yonemitsu, Y., Yoshida, K. et al. Impact of deletion of envelope-related genes of recombinant Sendai viruses on immune responses following pulmonary gene transfer of neonatal mice. Gene Ther 14, 1017–1028 (2007). https://doi.org/10.1038/sj.gt.3302955

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  • DOI: https://doi.org/10.1038/sj.gt.3302955

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