Intranasal administration of the growth-compromised HSV-2 vector DeltaRR 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 DeltaRR. DeltaRR is delivered intranasally. It is not toxic in rats and mice. ICP10PK is expressed in the hippocampus of the DeltaRR-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 DeltaRR prevents kainic acid-induced seizures, neuronal loss, and inflammation, in both rats and mice. The data suggest that DeltaRR is a promising therapeutic platform for neurodegenerative diseases.
Laing
Jennifer M
JM
Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, 655 W. Baltimore Street, Baltimore, MD 21201-1559, USA.
Gober
Michael D
MD
Golembewski
Erin K
EK
Thompson
Scott M
SM
Gyure
Kymberly A
KA
Yarowsky
Paul J
PJ
Aurelian
Laure
L
D000281:Administration, Intranasal; D000818:Animals; D002522:Chlorocebus aethiops; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D018258:Herpesvirus 2, Human / Q000235:genetics*; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism; D006801:Humans; D007608:Kainic Acid / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects*; D009924:Organ Culture Techniques; D016716:PC12 Cells; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000517:prevention & control*; D017384:Sequence Deletion; D016896:Treatment Outcome; D014709:Vero Cells
D007608:Kainic Acid