Article

Antioxidant gene therapy can protect hearing and hair cells from ototoxicity.

Department of Otolaryngology, Kansai Medical University, 10-15 Fumizono-cho, Moriguchi, Osaka 570-8506, Japan.
Molecular Therapy (impact factor: 6.87). 03/2004; 9(2):173-81. DOI:10.1016/j.ymthe.2003.11.020 pp.173-81
Source: PubMed

ABSTRACT Aminoglycosides are commonly used antibiotics that often induce ototoxicity leading to permanent hair cell loss and hearing impairment. The ototoxic effects of aminoglycosides have been linked to oxidative stress. To determine the feasibility of antioxidant gene therapy for protecting the inner ear against aminoglycoside-induced oxidative stress, we used adenoviral vectors for overexpression of catalase, Cu/Zn superoxide dismutase (SOD1), and Mn superoxide dismutase (SOD2). We inoculated adenoviruses designated Ad.cat, Ad.SOD1, and Ad.SOD2 into the left guinea pig cochlea. Five days later, an ototoxic combination of kanamycin and ethacrynic acid was systemically administered. Artificial perilymph and adenovirus without a gene cassette (Ad.null) were used as controls. Biochemical analysis showed significant increase in catalase and a moderate elevation in SOD2 levels in tissues of the cochlea inoculated with the respective vectors. Auditory brain-stem responses were measured to monitor hearing thresholds. Animals were sacrificed 7 days after the ototoxic insult and their hair cells counted. Hair cells and hearing thresholds were significantly protected by Ad.cat and Ad.SOD2, while results with Ad.SOD1 were inconsistent. Control ears showed no significant protective effects. The results demonstrate that the expression of functional enzymes in the inner ear is feasible using adenoviral-mediated gene delivery. Furthermore, they confirm that reactive oxygen species contribute to aminoglycoside ototoxicity and suggest antioxidant gene therapy as a potential therapeutic strategy to reduce inner ear oxidative stress.

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Keywords

adenoviral-mediated gene delivery
 
aminoglycoside ototoxicity
 
aminoglycoside-induced oxidative stress
 
antioxidant gene therapy
 
Auditory brain-stem responses
 
Biochemical analysis
 
cochlea inoculated
 
Control ears
 
Cu/Zn superoxide dismutase
 
gene cassette
 
Hair cells
 
hearing thresholds
 
induce ototoxicity
 
inner ear oxidative stress
 
Mn superoxide dismutase
 
moderate elevation
 
ototoxic effects
 
oxidative stress
 
potential therapeutic strategy
 
significant protective effects
 

Kohei Kawamoto