¹NYU Cancer Institute and the NYU Gene Therapy Center, Department of Pathology, NYU School of Medicine, New York University, New York, NY, USA

Correspondence: Dr D Meruelo, NYU Cancer Institute and the NYU Gene Therapy Center, NYU School of Medicine, 550 First Avenue, New York, NY 10016, USA. E-mail: merued01@med.nyu.edu

Received 3 June 2008; Revised 15 August 2008; Accepted 16 August 2008; Published online 25 September 2008.

Abstract

A major concern of using viral gene therapy is the potential for uncontrolled vector propagation and infection that might result in serious deleterious effects. To enhance the safety, several viral vectors, including vectors based on Sindbis virus, were engineered to lose their capability to replicate and spread after transduction of target cells. Such designs, however, could dramatically reduce the therapeutic potency of the viral vectors, resulting in the need for multiple dosages to achieve treatment goals. Earlier, we showed that a replication-defective (RD) Sindbis vector achieved specific tumor targeting without any adverse effects in vivo. Here, we present a replication-competent Sindbis viral vector that has an hsvtk suicide gene incorporated into ns3, an indispensable non-structural gene for viral survival. The capability of viral propagation significantly increases tumor-specific infection and enhances growth suppression of tumor compared with the conventional RD vectors. Furthermore, in the presence of the prodrug ganciclovir, the hsvtk suicide gene serves as a safety mechanism to prevent uncontrolled vector propagation. In addition to suppressing vector propagation, toxic metabolites, generated by prodrug activation, could spread to neighboring uninfected tumor cells to further enhance tumor killing.