Drug inducible transgene expression in brain using a herpes simplex virus vector.
The ability to regulate transgene expression is likely to be important in the use of gene transfer to treat diseases of the central nervous system (CNS). In order to achieve regulatable gene expression we created a replication-incompetent genomic herpes simplex vector containing a RU486-inducible transactivator and a lacZ reporter gene under transcriptional control of a minimal promoter. Reporter gene expression from the vector was regulated by administration of RU486 in vitro and in vivo. In cell culture half maximal expression was achieved with 10(-8) M RU486, and maximal expression was achieved by 24 h. Following stereotactic inoculation of the vector into rat hippocampus, expression was increased 150-fold by i.p. administration of RU486. This demonstrates that the RU486 system functions as a tight on/off switch for regulating expression of a transgene delivered to the brain via an HSV vector.
Oligino
T
T
Department of Molecular Genetics and Biochemistry, University of Pittsburgh School of Medicine, PA 15261, USA.
Poliani
P L
PL
Wang
Y
Y
Tsai
S Y
SY
O'Malley
B W
BW
Fink
D J
DJ
Glorioso
J C
JC
D000818:Animals; D001921:Brain / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage*; D006624:Hippocampus; D006727:Hormone Antagonists / Q000494:pharmacology*; D007150:Immunohistochemistry; D007267:Injections; D007763:Lac Operon / Q000235:genetics; D008297:Male; D015735:Mifepristone / Q000494:pharmacology*; D010957:Plasmids; D051381:Rats; D017207:Rats, Sprague-Dawley; D018139:Simplexvirus; D019076:Transgenes; D001616:beta-Galactosidase / Q000235:genetics
D006727:Hormone Antagonists; D015735:Mifepristone; D001616:beta-Galactosidase