医学Line-Derived Neurotrophic Factor.pdfVIP

HUMAN GENE THERAPY 10:813± 823 (March 20, 1999) Mary Ann Liebert, Inc. Hair Cell Protection from Aminoglycoside Ototoxicity by Adenovirus-Mediated Overexpression of Glial Cell Line-Derived Neurotrophic Factor MASAO YAGI, 1,2 ELLA MAGAL,3 ZEQI SHENG,3 KATHLEEN A. ANG,1 and YEHOASH RAPHAEL 1 ABSTRAC T Aminoglycosides are commonly used antimicrobial drugs that often have ototoxic side effects. The ototoxic- ity often involves permanent loss of cochlear hair cells (HCs). Neurotrophic factors have been shown to pro- tect 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 hu- man GDNF gene into guinea pig cochleae via the round window membrane 4 days prior to injection of amino- glycosides. Control groups showed little or no negative influence of the viral inoculation on cochlear struc- ture 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 feasi- bility 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. OVERVIEW SUMMARY INTRODUC TION Sensory hair cells in the mammalian inner ear do not re- EAFNESS AFFECTS more than 30 million Americans (Silver- generate following trauma-induced degeneration. There- Dstein et al., 1992). Sensorineural hearing loss results from fore, aminoglycoside-induced hair cell loss results in a per- a variety of causes such as exposure to intense sounds, infec- ma