Characterization of a semi-replicative gene delivery system allowing propagation of complementary
defective retroviral vectors.
Trajcevski S, Solly SK, Frisen C, Trenado A, Cosset FL, Klatzmann D.
de biologie et therapeutiques des pathologies immunitaires, CNRS UMR7087, Universite Pierre et Marie Curie, Groupe hospitalier
Pitie-Salpetriere, 83 boulevard de l'hopital, 75651 Paris cedex 13, France.
BACKGROUND: Recently, 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. METHODS: The semi-replication-competent
retroviral vector system is based on two transcomplementing replication-defective retroviral vectors termed gag-pol vector
(GPv) and env vector (Ev). Vector propagation was monitored in vitro and in solid tumors 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. RESULTS: 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. CONCLUSIONS: 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 tumors 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 in vitro studies and allows envisioning its further development for cancer
gene therapy. Copyright (c) 2004 John Wiley & Sons, Ltd.