Selective elimination of recombinant genes in vivo with a suicide retroviral vector.
The ability to express recombinant genes in vivo offers potential new treatments for human disease if questions of safety and toxicity can be addressed. Complications of gene transfer could include, for example, overexpression of introduced genes for growth or angiogenic factors or insertional mutagenesis, both of which could cause uncontrolled cell growth. We report the development of a suicide retroviral vector that provides a method to eliminate cells undergoing rapid growth in vivo. A murine amphotropic retroviral vector was constructed in which the gene for herpesvirus thymidine kinase was included to render proliferating cells sensitive to ganciclovir, and the Escherichia coli beta-galactosidase gene served as a reporter. This vector's efficacy was first assessed in vitro, and beta-galactosidase activity was abolished in several cell lines after treatment with ganciclovir. In vivo, a transplantable murine CT26 adenocarcinoma whose cells were transduced with this vector regressed completely after administration of ganciclovir. In contrast, expression in nondividing cells within rabbit arteries transduced by retroviral infection in vivo was unaffected. This suicide vector therefore eliminates transformed cells but allows survival of normal nondividing cells that express its specific recombinant genes in vivo, and may thus improve the safety and efficacy of gene transfer into living organisms.
Plautz
G
G
Howard Hughes Medical Institute, University of Michigan Medical Center, Department of Internal Medicine, Ann Arbor 48109-0650.
Nabel
E G
EG
Nabel
G J
GJ
D000230:Adenocarcinoma / Q000628:therapy; D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D002874:Chromosome Mapping; D015774:Ganciclovir / Q000627:therapeutic use; D015967:Gene Expression Regulation, Viral; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics; D006564:Herpesviridae; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D016254:Mutagenesis, Insertional; D011817:Rabbits; D013937:Thymidine Kinase / Q000096:biosynthesis; D014161:Transduction, Genetic; D001616:beta-Galactosidase / Q000096:biosynthesis
D013937:Thymidine Kinase; D001616:beta-Galactosidase; D015774:Ganciclovir