Characterization of a semi-replicative gene delivery system allowing propagation of complementary defective retroviral vectors.
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.
Trajcevski
Stéphane
S
Laboratoire de biologie et thérapeutiques des pathologies immunitaires, CNRS UMR7087, Université Pierre et Marie Curie, Groupe hospitalier Pitié-Salpêtrière, 83 boulevard de l'hôpital, 75651 Paris cedex 13, France.
Solly
Sounkary K
SK
Frisén
Charlotte
C
Trenado
Aurélie
A
Cosset
François-Loïc
FL
Klatzmann
David
D
D000818:Animals; D016026:Bone Marrow Transplantation; D002460:Cell Line; D004261:DNA Replication; D018014:Gene Transfer Techniques; D017930:Genes, Reporter; D005822:Genetic Vectors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D051381:Rats; D012190:Retroviridae / Q000235:genetics* / Q000378:metabolism; D014161:Transduction, Genetic; D019076:Transgenes