EFFECT OF EXOGENOUS NERVE GROWTH-FACTOR ON NEUROTOXICITY OF AND NEURONAL GENE DELIVERY BY A HERPES-SIMPLEX AMPLICON VECTOR IN THE RAT-BRAIN

We have previously shown that local destruction of neural tissue by wi ld-type herpes simplex virus type 1 (HSV-1) is attenuated by intracere bral infusion of nerve growth factor (NGF). To investigate the effect of NGF on the extent of neurolysis and efficacy of neuronal gene trans fer mediated by an HSV-1 amplicon vector system in vivo, rats were ste reotaxically injected in the striatum with an amplicon preparation, pH SVlac. This amplicon contains the Escherichia coil lacZ gene under the transcriptional control of the HSV-1 immediate early 4/5 promoter and is packaged by an HSV-1 helper virus carrying a deletion in the immed iate early 3 gene. Vector injection was followed by continuous intrace rebral infusion of NGF-beta (total dose 5 mu g) or vehicle solution ov er 7 days. Animals were sacrificed at the end of the 7-day infusion pe riod for histological analysis of the brains. A distinct zone of infla mmation and necrosis surrounded the injection site in all vector-inocu lated animals. The volume of striatal tissue destruction was significa ntly smaller in NGF-treated animals (1.27 +/- 0.19 mm(3); mean +/- SEM ) than in the vehicle-treated controls (2.16 +/- 0.37 mm(3); P < 0.05 by t-test). Immunohistochemical staining for HSV and beta-galactosidas e (beta-Gal) in vehicle-treated animals revealed that many striatal ce lls harbored HSV antigens 3,678 +/- 636), but only a small number expr essed the reporter gene at 7 days post-injection (294 +/- 60). NGF inf usion did not significantly affect the number of HSV-immunoreactive ce lls (4,224 +/- 618), or the number of cells expressing beta-Gal (330 /- 72) at this time. In some animals in both groups, a disseminated pa ttern of HSV immunoreactivity and reporter gene expression was seen th roughout the brain. We conclude that exogenous NGF reduces the local c ytopathologic effects of this HSV-1-derived vector in the rat striatum , but does not affect the number of HSV-immunoreactive cells or the sh ort-term expression of the transgene.