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 × 1010genome 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.
Division of Genetic Therapeutics, Jichi Medical University, Tochigi, Japan; Department of Otolaryngology, Jichi Medical University, Tochigi, Japan; Department of Otolaryngology, Peking University First Hospital, Beijing, China.
Yuhe
Y
Liu
Division of Genetic Therapeutics, Jichi Medical University, Tochigi, Japan; Department of Molecular Therapy, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan. Electronic address: t-okada@ncnp.go.jp.
Takashi
T
Okada
Department of Physiology, Jichi Medical University, Tochigi, Japan.
Kuniko
K
Shimazaki
Department of Neurobiology, Northeastern Ohio Universities College of Medicine, Rootstown, Ohio, USA.
Kianoush
K
Sheykholeslami
Division of Genetic Therapeutics, Jichi Medical University, Tochigi, Japan.
Tatsuya
T
Nomoto
Division of Neurology, Department of Medicine, Jichi Medical University, Tochigi, Japan.
Shin-Ichi
SI
Muramatsu
Division of Genetic Therapeutics, Jichi Medical University, Tochigi, Japan.
Hiroaki
H
Mizukami
Division of Genetic Therapeutics, Jichi Medical University, Tochigi, Japan.
Akihiro
A
Kume
Department of Otolaryngology, Peking University First Hospital, Beijing, China.
Shuifang
S
Xiao
Department of Otolaryngology, Jichi Medical University, Tochigi, Japan.
Keiichi
K
Ichimura
Division of Genetic Therapeutics, Jichi Medical University, Tochigi, Japan. Electronic address: kozawa@jichi.ac.jp.
Keiya
K
Ozawa