Oncogenesis following delivery of a non-primate lentiviral gene therapy vector to fetal mice

Top of pageAbstract Gene therapy by use of integrating vectors carrying therapeutic transgene sequences offers the potential for a permanent cure of genetic diseases due to the ability of these vectors to integrate in a stable manner into the patients chromosomes. However, three cases of T-cell leukaemia have been identified almost 3 years after retrovirus gene therapy for X-linked severe combined immune deficiency. In the two cases investigated to date, vector insertion into the LMO-2 locus was implicated in leukaemogenesis. The third case is currently under investigation (http://afssaps.sante.fr/ang/indang.htm). This has demonstrated that a more profound understanding is required of the genetic and molecular effects imposed by integrating vectors or transgene expression on the host, and has confirmed the need for in vivo models to test for retro- and lentiviral vector safety prior to clinical application. Our previous work has shown that widespread and efficient gene transfer is achievable with different lentivirus vectors following administration in utero to day 16 mouse fetuses. In the present study, we describe the long-term effects on mice after administration of a third generation EIAV lentivirus originating from Oxford BioMedica Ltd[1] with the observation of a high frequency of hepatocellular carcinomas following in utero injection, while in a similar study no tumours were observed using an HIV vector. This system provides a potentially sensitive in vivo model to investigate the molecular mechanisms of virus induced oncogenesis and to serve as an in vivo system for safety testing of integrating vectors in preparation for clinical applications.