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Adeno-associated virus vector-mediated bcl-2 gene transfer into post-ischemic gerbil brain in vivo: prospects for gene therapy of ischemia-induced neuronal death

Gene Therapy volume 7, pages 1244–1249 (2000)Cite this article

Abstract

The proto-oncogene bcl-2 is known as an anti-apoptotic gene that confers the ability to block neuronal cell death after transient ischemia. In order to examine whether the bcl-2 gene can be used for protection of ischemic brain injury, we generated adeno-associated virus (AAV) vectors capable of expressing human bcl-2. Replication-defective AAV vectors were found effectively to transfer and express bcl-2 gene in the gerbil hippocampal neurons. Transduction with AAV bcl-2 5 days before forebrain ischemia prevented the DNA fragmentation in the CA1 neurons that is commonly associated with ischemia-induced cell death. Furthermore, the application of AAV bcl-2 as late as 1 h following an ischemic insult also prevented DNA fragmentation in CA1 neurons. These results suggest that the bcl-2 protein has neuroprotective functions that inhibit ischemic cell death and demonstrate the potential of AAV bcl-2 for use in post-ischemic gene therapy in the brain.

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Acknowledgements

pB4 was kindly supplied by Dr Y Tsujimoto, Department of Genetics, Faculty of Medicine, Osaka University. This work was supported in part by Grants in Aid from the Ministry of Education, Science and Culture of Japan (10680749); by grants from the Ministry of Health and Welfare of Japan (H10-genome-026); and from Special Coordination Funds for promoting Science and Technology of STA. We thank Ms Y Hirano and Mr T Mizui for their technical assistance.

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Authors and Affiliations

  1. Department of Physiology, Jichi Medical School, Minamikawachi-machi, Minamikawachi-machi, Tochigi, Japan

    K Shimazaki & N Kawai

  2. Division of Genetic Therapeutics, Center for Molecular Medicine, Jichi Medical School, Minamikawachi-machi, Tochigi, Japan

    M Urabe & K Ozawa

  3. Avigen, Inc., Alameda, CA, USA

    J Monahan

  4. Department of Hematology, Jichi Medical School, Minamikawachi-machi, Tochigi, Japan

    K Ozawa

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  1. K Shimazaki
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  2. M Urabe
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  4. K Ozawa
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  5. N Kawai
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Shimazaki, K., Urabe, M., Monahan, J. et al. Adeno-associated virus vector-mediated bcl-2 gene transfer into post-ischemic gerbil brain in vivo: prospects for gene therapy of ischemia-induced neuronal death. Gene Ther 7, 1244–1249 (2000). https://doi.org/10.1038/sj.gt.3301211

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