HSV vector-delivery of GDNF in a rat model of PD: partial efficacy obscured by vector toxicity

Herpes simplex virus (HSV)-derived vectors have been suggested for potential use in gene therapy for Parkinson's disease (PD). HSV naturally infects adult neuronal cells and possesses a large genome for the insertion of transgenes. In the present study, we have used two different HSV constructs to deliver glial cell line-derived neurotrophic factor (GDNF) to the striatum, and to assess the neuroprotective effects of the GDNF product in an intrastriatal 6-hydroxydopamine lesion model. One construct is blocked for IE gene expression whereas the other is deleted in the thymidine kinase gene. Both constructs induced a significant protection of the dopaminergic neurons in the substantia nigra from the lesions, whereas only one induced a transient behavioural recovery in amphetamine-induced rotation. Unexpectedly, the more deleted virus caused the greater toxicity. This was found to be due to the way the vector was purified. The issue of toxicity, which might account for the variable functional effects, needs resolving prior to therapeutic application of these vectors.