title: Protection against aminoglycoside-induced ototoxicity by regulated AAV vector-mediated GDNF gene transfer into the cochlea.
abstract: Since standard aminoglycoside treatment progressively causes hearing disturbance with hair cell degeneration, systemic use of the drugs is limited. Adeno-associated virus (AAV)-based vectors have been of great interest because they mediate stable transgene expression in a variety of postmitotic cells with minimal toxicity. In this study, we investigated the effects of regulated AAV1-mediated glial cell line-derived neurotrophic factor (GDNF) expression in the cochlea on aminoglycoside-induced damage. AAV1-based vectors encoding GDNF or vectors encoding GDNF with an rtTA2s-S2 Tet-on regulation system were directly microinjected into the rat cochleae through the round window at 5 x 10(10) genome copies/body. Seven days after the virus injection, a dose of 333 mg/kg of kanamycin was subcutaneously given twice daily for 12 consecutive days. GDNF expression in the cochlea was confirmed and successfully modulated by the Tet-on system. Monitoring of the auditory brain stem response revealed an improvement of cochlear function after GDNF transduction over the frequencies tested. Damaged spiral ganglion cells and hair cells were significantly reduced by GDNF expression. Our results suggest that AAV1-mediated expression of GDNF using a regulated expression system in the cochlea is a promising strategy to protect the cochlea from aminoglycoside-induced damage.
authors.affiliation: Division of Genetic Therapeutics, Jichi Medical University, Tochigi, Japan.
authors.forename: Yuhe
authors.initials: Y
authors.lastname: Liu
authors.forename: Takashi
authors.initials: T
authors.lastname: Okada
authors.forename: Kuniko
authors.initials: K
authors.lastname: Shimazaki
authors.forename: Kianoush
authors.initials: K
authors.lastname: Sheykholeslami
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Nomoto
authors.forename: Shin-Ichi
authors.initials: S
authors.lastname: Muramatsu
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Mizukami
authors.forename: Akihiro
authors.initials: A
authors.lastname: Kume
authors.forename: Shuifang
authors.initials: S
authors.lastname: Xiao
authors.forename: Keiichi
authors.initials: K
authors.lastname: Ichimura
authors.forename: Keiya
authors.initials: K
authors.lastname: Ozawa
mesh_terms: D000617:Aminoglycosides / Q000633:toxicity*; D000818:Animals; D003051:Cochlea / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D000229:Dependovirus / Q000235:genetics; D005822:Genetic Vectors / Q000235:genetics; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000235:genetics / Q000502:physiology*; D006198:Hair Cells, Auditory / Q000378:metabolism; D034381:Hearing Loss / Q000139:chemically induced / Q000235:genetics / Q000628:therapy; D007150:Immunohistochemistry; D008297:Male; D010957:Plasmids / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D019076:Transgenes / Q000235:genetics
chemical_list: D000617:Aminoglycosides; D051100:Glial Cell Line-Derived Neurotrophic Factor