Intranasal administration of the growth-compromised HSV-2 vector ΔRR prevents kainate-induced seizures and neuronal loss in rats and mice

Identification of targets and delivery platforms for gene therapy of neurodegenerative disorders is a clinical challenge. We describe a novel paradigm in which the neuroprotective gene is the herpes simplex virus type 2 (HSV-2) antiapoptotic gene ICP10PK and the vector is the growth-com promised HSV-2 mutant ARR. ARR is delivered intranasally. It is not toxic in rats and mice. ICP10PK is expressed in the hippocampus of the ARR-treated animals for at least 42 days in the absence of virus replication and late virus gene expression. Its expression is regulated by an AP-1 amplification loop. Intranasally delivered ARR prevents kainic acid-induced seizures, neuronal loss, and inflammation, in both rats and mice. The data suggest that ARR is a promising therapeutic platform for neurodegenerative diseases.