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Adenovirus-mediated overexpression of a gene prevents hearing loss and progressive inner hair cell loss after transient cochlear ischemia in gerbils

Gene Therapy volume 10, pages 426–433 (2003)Cite this article

Abstract

The use of adenoviral vectors has recently provided a novel strategy for direct gene transfer into the cochlea. In this study, we assessed the utility of an adenoviral vector expressing glial-cell-derived neurotrophic factor (GDNF) in ischemia–reperfusion injury of the gerbil cochlea. The vector was injected through the round window 4 days before ischemic insult. The distribution of a reporter transgene was confirmed throughout the cochlea from the basal to the apical turn and Western blot analysis indicated significant upregulation of GDNF protein 11 days following virus inoculation. Hearing ability was assessed by sequentially recording compound action potentials (CAP), and the degree of hair cell loss in the organ of Corti was evaluated in specimens stained with rhodamine-phalloidin and Hoechst 33342. On the seventh day of ischemia, the CAP threshold shift and inner hair cell loss were remarkably suppressed in the Ad-GDNF group compared with the control group. These results suggest that adenovirus-mediated overexpression of GDNF is useful for protection against hair cell damage, which otherwise eventually occurs after transient ischemia of the cochlea.

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References

  1. Gussen R . Sudden deafness of vascular origin: a human temporal bone study. Ann Otol Rhinol Laryngol 1976; 85: 94–100.

    Article  CAS  Google Scholar 

  2. Cole RR, Jahrsdoerfer RA . Sudden hearing loss: an update. Am J Otol 1988; 9: 211–215.

    CAS  PubMed  Google Scholar 

  3. Kim JS et al. Internal auditory artery infarction: clinicopathologic correlation. Neurology 1999; 52: 40–44.

    Article  CAS  Google Scholar 

  4. Hata R et al. Differential vulnerability in the hindbrain neurons and local cerebral blood flow during bilateral vertebral occlusion in gerbils. Neuroscience 1993; 56: 423–439.

    Article  CAS  Google Scholar 

  5. Hakuba N et al. Hearing loss and glutamate efflux in the perilymph following transient hindbrain ischemia in gerbils. J Comp Neurol 2000; 418: 217–226.

    Article  CAS  Google Scholar 

  6. Watanabe F et al. Hypothermia prevents hearing loss and progressive hair cell loss after transient cochlear ischemia in gerbils. Neuroscience 2000; 102: 639–645.

    Article  Google Scholar 

  7. Koga K et al. Transient cochlear ischemia causes delayed cell death in the organ of Corti and the spiral ganglion: an experimental study in gerbils. J Comp Neurol (in press).

  8. Gaschwind MD et al. Defective HSV-1 vector expression BDNF in auditory ganglia elicits neurite outgrowth: model of treatment of neuron loss following cochlear degeneration. Hum Gene Ther 1994; 7: 173–182.

    Article  Google Scholar 

  9. Lalwani AK et al. Development of in vivo gene therapy for hearing disorders: introduction of adeno-associated virus into the cochlea of the guinea pig. Gene Ther 1996; 3: 588–592.

    CAS  PubMed  Google Scholar 

  10. Raphael Y, Frisancho JC, Roessler BJ . Adenoviral-mediated gene transfer into guinea pig cochlea cells in vivo. Neurosci Lett 1996; 207: 137–141.

    Article  CAS  Google Scholar 

  11. Keithley EM et al. GDNF protects the cochlea against noise damage. Neuroreport 1998; 9: 2183–2187.

    Article  CAS  Google Scholar 

  12. Yagi M et al. Hair cell protection from aminoglycoside otoxicity by adenovirus-mediated overexpression of glial cell line-derived neurotrophic factor. Hum Gene Ther 1999; 10: 813–823.

    Article  CAS  Google Scholar 

  13. Lin LF, Zhang TJ, Collins F, Armes LG . Purification and initial characterization of rat B49 glial cell line-derived neurotrophic factor. J Neurochem 1994; 63: 758–768.

    Article  CAS  Google Scholar 

  14. Lin LF et al. GDNF a glial cell line-derived neurotrophic factor from midbrain dopaminergic neurons. Science 1993; 260: 1130–1132.

    Article  CAS  Google Scholar 

  15. Abe K, Setoguchi Y, Hayashi T, Itoyama Y . In vivo adenovirus-mediated gene transfer and the expression in ischemic and reperfused rat brain. Brain Res 1997; 763: 191–201.

    Article  CAS  Google Scholar 

  16. Wang Y et al. Glial cell line-derived neurotrophic factor protects against ischemia-induced injury in the cerebral cortex. J Neurosci 1997; 17: 4341–4348.

    Article  CAS  Google Scholar 

  17. Kitagawa H et al. Reduction of ischemic brain injury by topical application of glial cell line-derived neurotrophic factor after permanent middle cerebral artery occlusion in rats. Stroke 1998; 29: 1417–1422.

    Article  CAS  Google Scholar 

  18. Kitagawa H et al. Adenovirus-mediated gene transfer of glial cell line-derived neurotrophic factor prevents ischemic brain injury after transient middle cerebral artery occlusion in rats. J Cereb Blood Flow Metab 1999; 19: 1336–1344.

    Article  CAS  Google Scholar 

  19. Harmann DM et al. Adenovirus-mediated GDNF and CNTF pretreatment protects against striatal injury following transient middle cerebral artery occlusion in mice. Neurobiol Dis 2001; 8: 655–666.

    Article  Google Scholar 

  20. Yagi T et al. Rescue of ischemic brain injury by adenoviral gene transfer of glial cell line-derived neurotrophic factor after transient global ischemia in gerbils. Brain Res 2000; 885: 273–282.

    Article  CAS  Google Scholar 

  21. Sakurai M et al. Adenovirus-mediated glial cell line-derived neurotrophic factor gene delivery reduces motor neuron injury after transient spinal cord ischemia in rabbits. J Thorac Cardiovasc Surg 2000; 120: 1148–1157.

    Article  CAS  Google Scholar 

  22. Ylikoski J et al. Guinea pig auditory neurons are protected by glial cell line-derived growth factor from degeneration after noise trauma. Hear Res 1998; 124: 17–26.

    Article  CAS  Google Scholar 

  23. Stöver T, Yagi M, Raphael Y . Transduction of the contralateral ear after adenovirus-mediated cochlear gene transfer. Gene Ther 2000; 7: 377–383.

    Article  Google Scholar 

  24. Stöver T et al. Glial cell line-derived neurotrophic factor (GDNF) and its receptor complex are expressed in the auditory nerve of the mature rat cochlea. Hear Res 2001; 155: 143–151.

    Article  Google Scholar 

  25. Hawkins Jr JE et al. Hearing loss and cochlear pathology in monkeys after noise exposure. Acta Otolaryngol 1976; 81: 337–343.

    Article  Google Scholar 

  26. Schacht J . Molecular mechanisms of drug-induced hearing loss. Hear Res 1986; 22: 297–304. Review.

    Article  CAS  Google Scholar 

  27. Dallos P . Outer hair cells: the inside story. Ann Otol Rhinol Laryngol Suppl 1997; 168:16–22.

    CAS  PubMed  Google Scholar 

  28. Puel JL et al. Excitatory amino acid antagonists protect ochlear auditory neurons from excitotoxicity. J Comp Neurol 1994; 341: 241–256.

    Article  CAS  Google Scholar 

  29. Seidman MD, Quirk WS . The protective effects of tirilated mesylate (U74006F) on ischemic and reperfusion-induced cochlear damage. Otolaryngol Head Neck Surg 1991; 105: 511–516.

    Article  CAS  Google Scholar 

  30. Lopez-Gonzalez MA et al. Melatonin and other antioxidants prolong the postmortem activity of the outer hair cells of the organ of Corti: its relation to the type of death. J Pineal Res 1999; 27: 73–77.

    Article  CAS  Google Scholar 

  31. Ho TW et al. TGFbeta trophic factors differentially modulate motor axon outgrowth and protection from excitotoxicity. Exp Neurol 2000; 161: 664–675.

    Article  CAS  Google Scholar 

  32. Brene S et al. Regulation of GluR2 promoter activity by neurotrophic factors via a neuron-restrictive silencer element. Eur J Neurosci 2000; 12: 1525–1533.

    Article  CAS  Google Scholar 

  33. Kloth S, Suter-Crazzolara C . Modulation of renal blood vessel formation by glial cell line-derived neurotrophic factor. Microvasc Res 2000; 59:190–194.

    Article  CAS  Google Scholar 

  34. Kho ST, Pettis RM, Mhatre AN, Lalwani AK . Safety of adeno-associated virus as cochlear gene transfer vector: analysis of distant spread beyond injected cochleae. Mol Ther 2000; 2: 368–373.

    Article  CAS  Google Scholar 

  35. Miyake S et al. Efficient generation of recombinant adenoviruses using adenovirus DNA-terminal protein complex and a cosmid bearing the full-length virus genome. Proc Natl Acad Sci 1996; 93: 1320–1324.

    Article  CAS  Google Scholar 

  36. Watabe K et al. Rescue of lesioned adult rat spinal motoneurons by adenoviral gene transfer of glial cell line-derived neurotropic factor. J Neurosci Res 2000; 15: 511–519.

    Article  Google Scholar 

  37. Kanegae Y et al. Efficient gene activation in mammalian cells by using recombinant adenovirus expressing site-specific Cre recombinase. Nucleic Acids Res 1995; 23: 3816–3821.

    Article  CAS  Google Scholar 

  38. Bobbin RP, Konishi T . Action of cholinergic and anticholinergic drugs at the crossed olive-cochlear bundle-hair cell junction. Acta Otolaryngol 1974; 77: 55–65.

    Article  Google Scholar 

  39. Smith PK et al. Measurement of protein using bicinchoninic acid. Anal Biochem 1985; 150: 76–85.

    Article  CAS  Google Scholar 

  40. Tanaka J et al. Astrocytes prevent neuronal death induced by reactive oxygen and nitrogen species. Glia 1999; 28: 85–96.

    Article  CAS  Google Scholar 

  41. Hildesheimer M, Rubinstein CM, Creter D, Rubinstein M . Long-term electrode implantation for recording cochlear electrical activity in guinea pigs. Acta Otolaryngol 1979; 88: 37–40.

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Otolaryngology, Ehime University School of Medicine, Shigenobu-cho, Onsen-gun, Ehime, Japan

    N Hakuba, J Hyodo, M Taniguchi & K Gyo

  2. Department of Molecular Neuropathology, Tokyo Metropolitan Institute for Neuroscience, Tokyo, Japan

    K Watabe

  3. Department of Gene Therapy, Institute of DNA Medicine, Tokyo, Japan

    T Ohashi & Y Eto

  4. Department of Pediatrics, Jikei University School of Medicine, Tokyo, Japan

    T Ohashi & Y Eto

  5. Department of Physiology, Ehime University School of Medicine, Shigenobu-cho, Onsen-gun, Ehime, Japan

    L Yang, J Tanaka & R Hata

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  1. N Hakuba
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Hakuba, N., Watabe, K., Hyodo, J. et al. Adenovirus-mediated overexpression of a gene prevents hearing loss and progressive inner hair cell loss after transient cochlear ischemia in gerbils. Gene Ther 10, 426–433 (2003). https://doi.org/10.1038/sj.gt.3301917

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  • DOI: https://doi.org/10.1038/sj.gt.3301917

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