Regulated transgene delivery by ganciclovir in the brain without physiological alterations by a live attenuated herpes simplex virus vector.
The distribution of a live attenuated herpes simplex virus (betaH1)-mediated gene delivery into the central nervous system (CNS) was regulated by growth inhibition with ganciclovir (GCV) and the effect of this transgene expression system on the physiologic response was characterized by the acoustic startle response and its prepulse inhibition. We inoculated betaH1 expressing beta-galactosidase (beta-gal) driven by the latency associated transcripts promoter into the right caudate putamen of rats. Histochemical analysis demonstrated that the inoculation of betaH1 in the right caudate putamen resulted in a high level of beta-gal expression in the neurons of the area projecting to the inoculation site. On 14 days after inoculation without GCV-treatment, beta-gal activity localized in the anterior olfactory nucleus, frontal, insular, orbital, parietal, perirhinal, piriform cortices and the temporal region including the amygdala. In contrast, the distribution of beta-gal activity was regulated by the interval between virus inoculation and GCV-treatment and maintained after its cessation without significant alteration. The whole process of transgene expression did not influence the emotional behavior, indicating that this vector system is a suitable model for analyzing the transgene function or applying the gene therapy for the CNS diseases.
Fukuda
Yoshiko
Y
Department of Virology, Toyama Medical and Pharmaceutical University, 2630 Sugitani, Toyama 930-0194, Japan.
Yamamura
Jun-ichi
J
Uwano
Teruko
T
Nishijo
Hisao
H
Kurokawa
Masahiko
M
Fukuda
Masaji
M
Ono
Taketoshi
T
Shiraki
Kimiyasu
K
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D016503:Drug Delivery Systems / Q000379:methods; D015774:Ganciclovir / Q000008:administration & dosage*; D005822:Genetic Vectors / Q000008:administration & dosage* / Q000235:genetics; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D018139:Simplexvirus / Q000235:genetics / Q000378:metabolism*; D019076:Transgenes / Q000235:genetics / Q000502:physiology*; D001616:beta-Galactosidase / Q000032:analysis / Q000096:biosynthesis
D001616:beta-Galactosidase; D015774:Ganciclovir