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Obtention of replicative retroviral vectors efficiently expressing a marker or therapeutic gene in various cell lines and animal cancer models

Replicative retroviral vectors (RRVs) were designed and tested for their efficient expression of marker or therapeutic genes in tumour cell lines and animal cancer models. During the course of this project, it became clear that that the importance of restricting defective retroviral vector expression by means of tissue specific ligands or promoters was somewhat overshadowed by another key issue; their poor efficiency of gene transfer into cancer cells. The defective nature of the vectors constituted a major bottleneck of current cancer gene therapy, while we reasoned that because tumours are masses of rapidly dividing cells, they would be most efficiently transduced with vector systems allowing transgene propagation. We thus designed two replicative retrovirus -derived vector systems: one inherently replicative vector, and one defective vector propagated by a helper retrovirus. In vitro, both systems achieved very efficient transgene propagation. In immuno-competent mice, replicative vectors transduced >85% tumour cells, whereas defective vectors transduced <1%under similar conditions. The viral propagation could be efficiently blocked by azido-thymidine, in vitro and in vivo. In a model of established brain tumours treated with suicide genes, RRVs were approximately 1000 times more efficient than defective adenoviral vectors. These results demonstrate the advantage and potential of RRVs and strongly support their development for cancer gene therapy. We are currently evaluating their efficacy using different tumour models (glioblastoma and melanoma) and different suicide genes (HSV-TK and CD).

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UNiversite Pierre et Marie Curie - UMR7087
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