Split genome-based retroviral replicating vectors achieve efficient gene delivery and therapeutic effect in a human glioblastoma xenograft model
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The murine leukemia virus-based semi-retroviral replicatingvectors (MuLV-based sRRV) had been developed to improvesafety and transgene capacity for cancer gene therapy. However,despite the apparent advantages of the sRRV, improvementsin the in vivo transduction efficiency are still required todeliver therapeutic genes efficiently for clinical use. In this study,we established a gibbon ape leukemia virus (GaLV) envelopepseudotypedsemi-replication-competent retrovirus vector system(spRRV) which is composed of two transcomplementing replication-defective retroviral vectors termed MuLV-Gag-Pol andGaLV-Env. We found that the spRRV shows considerable improvementin efficiencies of gene transfer and spreading in bothhuman glioblastoma cells and pre-established human glioblastomamouse model compared with an sRRV system. When treatedwith ganciclovir after intratumoral injection of each vector systeminto pre-established U-87 MG glioblastomas, the group of miceinjected with spRRV expressing the herpes simplex virus type1-thymidine kinase (HSV1-tk) gene showed a survival rate of100% for more than 150 days, but all control groups ofmice (HSV1-tk/PBS-treated and GFP/GCV-treated groups) diedwithin 45 days after tumor injection. In conclusion, thesefindings sug-gest that intratumoral delivery of the HSV1-tkgene by the spRRV system is worthy of development inclinical trials for the treatment of malignant solid tumors.
Abstract
The murine leukemia virus-based semi-retroviral replicatingvectors (MuLV-based sRRV) had been developed to improvesafety and transgene capacity for cancer gene therapy. However,despite the apparent advantages of the sRRV, improvementsin the in vivo transduction efficiency are still required todeliver therapeutic genes efficiently for clinical use. In this study,we established a gibbon ape leukemia virus (GaLV) envelopepseudotypedsemi-replication-competent retrovirus vector system(spRRV) which is composed of two transcomplementing replication-defective retroviral vectors termed MuLV-Gag-Pol andGaLV-Env. We found that the spRRV shows considerable improvementin efficiencies of gene transfer and spreading in bothhuman glioblastoma cells and pre-established human glioblastomamouse model compared with an sRRV system. When treatedwith ganciclovir after intratumoral injection of each vector systeminto pre-established U-87 MG glioblastomas, the group of miceinjected with spRRV expressing the herpes simplex virus type1-thymidine kinase (HSV1-tk) gene showed a survival rate of100% for more than 150 days, but all control groups ofmice (HSV1-tk/PBS-treated and GFP/GCV-treated groups) diedwithin 45 days after tumor injection. In conclusion, thesefindings sug-gest that intratumoral delivery of the HSV1-tkgene by the spRRV system is worthy of development inclinical trials for the treatment of malignant solid tumors.
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