Basic research of malignant glioma-specific gene therapy by using very high titer retrovirus vectors

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Gene therapy for malignant glioma was done for the first time in the United States in 1992. They implanted PA317 (mouse) packaging cells, which produced the retrovirus vectors transduced the non-specific SV40 promoter, into the tumor beds of malignant glioma patients (Ram Z, et al : Nature Med, 1997). This procedure may induce not only the immunological xeno-transplantation reactions but also the serious side-effects into the normal divided cells. Therefore, we have repeated some basic research on brain-specific gene therapy controlled suicide gene (Herpes Simplex Virus thymidine kinase ; HSVtk) with promoter expressed Myelin basic protein (MBP) gene (J Neurosci Res 36, 1993). We transduced the Polyoma ori early region into the packaging cells produced retrovirus in order to obtain the high-titer retroviral vectors (Hum Gene Ther 9, 1998). And mouse brain tumor models were completely cured by these high-titer vectors (Gene Ther 5, 1998 ; Gene Ther 8, 2001 ; Human Cell 14, 2001). The sa … More fety test these vectors by using a common marmoset (primates) was approved as a confirmation experiment of the Minister of Education, Culture, Sports, Science and Technology on December 2, 2002. Now, we perform several in vitro safety studies of these high-titer brain-specific retroviral vector-producing (packaging) cells (master cells) and cryopreserve these master cells, and then take a plan of in vivo safety examinations by using common marmosets. Finally, we are planning clinical phase I studies of gene therapy for brain tumor patients in 2004.In addition, as these malignant gliomas showed high and low MBP-expressed gene, we identified MAGE-E1 gene, as one of the candidates for glioma-related genes, by using the SAGE(serial analysis of gene expression) method (Cancer Res 61, 2001 ; Gene 277, 2001). Now, we search the promoter expressing MAGE-E1 gene, and then will try a new glioma-specific gene therapy, which vectors were transduced this new promoter. Moreover, we will research the correlation between this MAGE-E1 gene appearance and major histocompatibility complexes (MHC) of glioma patients under agreement of the patient himself, according to "Ethics indication concerning human genome and gene analysis research". Less