Hearing and hair cells are protected by adenoviral gene therapy with TGF-β1 and GDNF

Kohei Kawamoto, Masao Yagi, Timo Stöver, Sho Kanzaki, Yehoash Raphael

Research output: Contribution to journalArticle

75 Citations (Scopus)

Abstract

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 β1 (TGF-β1), a ubiquitous cytokine. The aim of this study was to determine whether TGF-β1 receptors are expressed in the inner ear and whether a cocktail of GDNF and TGF-β1 transgenes provides enhanced protection of the inner ear against ototoxic trauma. Using RT-PCR analysis, we determined that both TGF-β1 receptors, type 1 and 2 are present in rat cochlea. We co-inoculated two adenoviral vectors, one encoding human TGF-β1 gene (Ad.TGF-β1) 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-β1 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-β1 can be used in combination to protect cochlear hair cells and hearing from ototoxic trauma.

Original languageEnglish
Pages (from-to)484-492
Number of pages9
JournalMolecular Therapy
Volume7
Issue number4
DOIs
Publication statusPublished - 2003 Apr 1

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Keywords

  • Cochlea
  • GDNF
  • Gene therapy
  • Guinea pig
  • Ototoxicity
  • Protection
  • TGF-β1

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery

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