Hearing and hair cells are protected by adenoviral gene therapy with TGF-beta1 and GDNF.
Glial cell line-derived neurotrophic factor (GDNF) overexpression in the inner ear can protect hair cells against degeneration induced by aminoglycoside ototoxicity. The protective efficiency of GDNF increases when it is combined with co-factors such as transforming growth factor beta1 (TGF-beta1), a ubiquitous cytokine. The aim of this study was to determine whether TGF-beta1 receptors are expressed in the inner ear and whether a cocktail of GDNF and TGF-beta1 transgenes provides enhanced protection of the inner ear against ototoxic trauma. Using RT-PCR analysis, we determined that both TGF-beta1 receptors, type 1 and 2 are present in rat cochlea. We co-inoculated two adenoviral vectors, one encoding human TGF-beta1 gene (Ad.TGF-beta1) and the other encoding human GDNF gene (Ad.GDNF) into guinea pig cochleae 4 days prior to injecting an ototoxic dose of aminoglycosides. Inoculated ears had better hearing and fewer missing inner hair cells after exposure to the aminoglycoside ototoxicity, as compared with controls and ears treated only with Ad.GDNF. Cochleae with TGF-beta1 overexpression exhibited fibrosis in the scala tympani regardless of the presence of GDNF. Our results suggest that the adenovirus-mediated overexpression of GDNF and TGF-beta1 can be used in combination to protect cochlear hair cells and hearing from ototoxic trauma.
Kresge Hearing Research Institute, Department of Otolaryngology-Head and Neck Surgery, The University of Michigan, Ann Arbor, Michigan 48109-0648, USA. yoash@umich.edu
Kohei
K
Kawamoto
Masao
M
Yagi
Timo
T
Stöver
Sho
S
Kanzaki
Yehoash
Y
Raphael
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D003051:Cochlea / Q000473:pathology; D016057:Evoked Potentials, Auditory, Brain Stem; D015316:Genetic Therapy; D005822:Genetic Vectors; D051100:Glial Cell Line-Derived Neurotrophic Factor; D006168:Guinea Pigs; D006198:Hair Cells, Auditory / Q000378:metabolism / Q000473:pathology*; D034381:Hearing Loss / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D006801:Humans; D008297:Male; D009414:Nerve Growth Factors / Q000235:genetics*; D051381:Rats; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics*; D053773:Transforming Growth Factor beta1
C495039:GDNF protein, human; C495041:Gdnf protein, rat; D051100:Glial Cell Line-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D018125:Receptors, Transforming Growth Factor beta; C508960:TGFB1 protein, human; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1