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

Semi-explicative retroviral vectors 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 their poor efficiency of gene transfer into cancer cells. Indeed, several cancer gene therapy studies have shown that replication-competent retroviral vectors represent a major improvement over replication-defective ones in terms of transgene propagation efficiency. However, this positive effect is somewhat spoiled by the increased risk of dissemination and oncogenesis that replication-competent retroviral vectors entail. To enhance both their integral safety and their transgene capacity, we developed a semi-replication-competent retroviral vector system.

The semi-replication-competent retroviral vector system is based on two trans-complementing replication-defective retroviral vectors termed gag-pol vector (GPv) and env vector (Ev). Vector propagation was monitored in vitro and in solid tumours in vivo, using different reporter transgenes for GPv and Ev. Systemic vector dissemination and leukemogenesis was assessed by direct intravenous vector injection and subsequent bone marrow transplantation, in MLV-sensitive mice.

In vitro and in vivo the semi-replication-competent retroviral vectors propagate transgenes almost as efficiently as replication-competent ones. The semi-replication-competent retroviral vector system does not lead to detectable dissemination or leukemogenesis as does the replication-competent vector or the parental virus. Additionally, the vector duo allows co-propagation of different transgenes as well as mobilization of a third replication-defective vector.

This study is an initial proof of principle for the use of complementary retroviral vectors to deliver and propagate transgenes in vitro and in solid tumours in vivo, but with reduced pathogenicity compared to its parental virus. In-between replication-defective and replication-competent retroviral vectors, this semi-replicative system offers good grounds for its application in vitro studies and allows envisioning its further development for cancer gene therapy.

Reported by

UNiversite Pierre et Marie Curie - UMR7087
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