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-compromised HSV-2 mutant ΔRR. ΔRR is delivered intranasally. It is not toxic in rats and mice. ICP10PK is expressed in the hippocampus of the ΔRR-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 ΔRR prevents kainic acid-induced seizures, neuronal loss, and inflammation, in both rats and mice. The data suggest that ΔRR is a promising therapeutic platform for neurodegenerative diseases.