Hair cell protection from aminoglycoside ototoxicity by adenovirus-mediated overexpression of glial cell line-derived neurotrophic factor.
Aminoglycosides are commonly used antimicrobial drugs that often have ototoxic side effects. The ototoxicity often involves permanent loss of cochlear hair cells (HCs). Neurotrophic factors have been shown to protect a variety of tissues, including HCs, from toxic trauma. To determine if glial cell line-derived neurotrophic factor (GDNF) can protect cochlear HCs from trauma, we inoculated an adenoviral vector encoding the human GDNF gene into guinea pig cochleae via the round window membrane 4 days prior to injection of aminoglycosides. Control groups showed little or no negative influence of the viral inoculation on cochlear structure and function. In contrast, ears that were inoculated with the GDNF vector had better hearing and fewer missing HCs after exposure to the ototoxins, as compared with controls. Our results demonstrate the feasibility of gene therapy for cochlear application and suggest that virus-mediated overexpression of GDNF may be developed as a valuable prevention against trauma-induced HC death.
Yagi
M
M
Kresge Hearing Research Institute, The University of Michigan, Ann Arbor 48109-0648, USA.
Magal
E
E
Sheng
Z
Z
Ang
K A
KA
Raphael
Y
Y
D000256:Adenoviridae / Q000235:genetics; D000617:Aminoglycosides; D000818:Animals; D000900:Anti-Bacterial Agents / Q000633:toxicity*; D001300:Audiometry, Evoked Response; D016923:Cell Death; D003051:Cochlea / Q000033:anatomy & histology / Q000378:metabolism; D018014:Gene Transfer Techniques; D017930:Genes, Reporter; D005822:Genetic Vectors; D051100:Glial Cell Line-Derived Neurotrophic Factor; D006168:Guinea Pigs; D006198:Hair Cells, Auditory / Q000378:metabolism*; D006319:Hearing Loss, Sensorineural / Q000517:prevention & control*; D007763:Lac Operon; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000627:therapeutic use; D012533:Scala Tympani / Q000378:metabolism
D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D051100:Glial Cell Line-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins