Protection against aminoglycoside-induced ototoxicity by regulated AAV vector-mediated GDNF gene transfer into the cochlea.
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.
Liu
Yuhe
Y
Division of Genetic Therapeutics, Jichi Medical University, Tochigi, Japan.
Okada
Takashi
T
Shimazaki
Kuniko
K
Sheykholeslami
Kianoush
K
Nomoto
Tatsuya
T
Muramatsu
Shin-Ichi
S
Mizukami
Hiroaki
H
Kume
Akihiro
A
Xiao
Shuifang
S
Ichimura
Keiichi
K
Ozawa
Keiya
K
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
D000617:Aminoglycosides; D051100:Glial Cell Line-Derived Neurotrophic Factor