title: A new approach with less damage: intranasal delivery of tetracycline-inducible replication-defective herpes simplex virus type-1 vector to brain.
abstract: Gene therapy holds great potential for treating neurological disorders. However, delivering gene vectors to the brain has been either invasive or inefficacious in most studies to date. The aim of this study was to develop a safe and efficacious strategy for delivering gene vectors to the brain. A tetracycline-inducible replication-defective herpes simplex virus type-1 vector, QR9TO-LacZ, was administered to rats intranasally. QR9TO-LacZ could infect primary cortical neurons and express the reporter gene without detectable replication. QR9TO-LacZ was observed in the olfactory bulb, hippocampus, striatum, cortex, medulla, cerebellum, ventricles, and nasal septum after intranasal administration. Expression of the reporter gene could be controlled effectively by tetracycline. In vitro, introduction of QR9TO-LacZ did not change the structure of transfected neurons. In vivo, QR9TO-LacZ did not increase apoptosis in neurons and did not alter levels of interleukin 6 and tumor necrosis factor α in the brain after intranasal delivery. Our data suggest that intranasally applied QR9TO-LacZ has a wide distribution and expresses the reporter gene in the brain under the control of tetracycline with less cytotoxicity than intravenous or stereotactic delivery methods.
authors.affiliation: Department of Neurology, Jinling Hospital, Nanjing University School of Medicine, 305 East Zhongshan Road, Nanjing 210002, Jiangsu Province, PR China.
authors.forename: Y
authors.initials: Y
authors.lastname: Jiang
authors.forename: N
authors.initials: N
authors.lastname: Wei
authors.forename: J
authors.initials: J
authors.lastname: Zhu
authors.forename: D
authors.initials: D
authors.lastname: Zhai
authors.forename: L
authors.initials: L
authors.lastname: Wu
authors.forename: M
authors.initials: M
authors.lastname: Chen
authors.forename: G
authors.initials: G
authors.lastname: Xu
authors.forename: X
authors.initials: X
authors.lastname: Liu
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001921:Brain / Q000166:cytology / Q000378:metabolism* / Q000648:ultrastructure / Q000821:virology; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D015967:Gene Expression Regulation, Viral / Q000187:drug effects*; D005822:Genetic Vectors; D018259:Herpesvirus 1, Human / Q000235:genetics / Q000378:metabolism*; D020287:In Situ Nick-End Labeling; D008297:Male; D046529:Microscopy, Electron, Transmission; D009474:Neurons / Q000378:metabolism / Q000502:physiology* / Q000648:ultrastructure / Q000821:virology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013752:Tetracycline / Q000494:pharmacology*; D013778:Tetrazolium Salts; D013844:Thiazoles; D013997:Time Factors; D014162:Transfection; D001616:beta-Galactosidase / Q000378:metabolism
chemical_list: D013778:Tetrazolium Salts; D013844:Thiazoles; D001616:beta-Galactosidase; C022616:thiazolyl blue; D013752:Tetracycline