Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Auditory hair cell replacement and hearing improvement by Atoh1 gene therapy in deaf mammals

Nature Medicine volume 11, pages 271–276 (2005)Cite this article

Abstract

In the mammalian auditory system, sensory cell loss resulting from aging, ototoxic drugs, infections, overstimulation and other causes is irreversible and leads to permanent sensorineural hearing loss. To restore hearing, it is necessary to generate new functional hair cells. One potential way to regenerate hair cells is to induce a phenotypic transdifferentiation of nonsensory cells that remain in the deaf cochlea. Here we report that Atoh1, a gene also known as Math1 encoding a basic helix-loop-helix transcription factor and key regulator of hair cell development, induces regeneration of hair cells and substantially improves hearing thresholds in the mature deaf inner ear after delivery to nonsensory cells through adenovectors. This is the first demonstration of cellular and functional repair in the organ of Corti of a mature deaf mammal. The data suggest a new therapeutic approach based on expressing crucial developmental genes for cellular and functional restoration in the damaged auditory epithelium and other sensory systems.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Hair cell elimination and Atoh1 expression in deaf cochleae.
Figure 2: Hair cells reappear in deaf ears treated with Ad.Atoh1.
Figure 3: New hair cells and nuclei in the deafened cochleae inoculated with Ad.Atoh1.
Figure 4: Cochleae analyzed with SEM at 4 weeks after Atoh1 treatment (a) or myosin VIIa immunocytochemistry at 5 weeks after treatment (c) and the respective contralateral ears (b and d).
Figure 5: Atoh1 treatment improves ABR thresholds.

Similar content being viewed by others

References

  1. Fekete, D.M. Cell fate specification in the inner ear. Current Opin. Neurobiol. 6, 533–541 (1996).

    Article  CAS  Google Scholar 

  2. Fekete, D.M. Making sense of making hair cells. Trends Neurosci. 23, 386 (2000).

  3. Torres, M. & Giraldez, F. The development of the vertebrate inner ear. Mech. Dev. 71, 5–21 (1998).

    Article  CAS  PubMed  Google Scholar 

  4. Bermingham, N.A. et al. Math1: an essential gene for the generation of inner ear hair cells. Science 284, 1837–1841 (1999).

    Article  CAS  PubMed  Google Scholar 

  5. Chen, P., Johnson, J.E., Zoghbi, H.Y. & Segil, N. The role of Math1 in inner ear development: Uncoupling the establishment of the sensory primordium from hair cell fate determination. Development 129, 2495–2505 (2002).

    Article  CAS  PubMed  Google Scholar 

  6. Shou, J., Zheng, J.L. & Gao, W.Q. Robust generation of new hair cells in the mature mammalian inner ear by adenoviral expression of Hath1. Mol. Cell Neurosci. 23, 169–179 (2003).

    Article  CAS  PubMed  Google Scholar 

  7. Kawamoto, K., Ishimoto, S., Minoda, R., Brough, D.E. & Raphael, Y. Math1 gene transfer generates new cochlear hair cells in mature guinea pigs in vivo. J. Neurosci. 23, 4395–4400 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Hasson, T., Heintzelman, M.B., Santos-Sacchi, J., Corey, D.P. & Mooseker, M.S. Expression in cochlea and retina of myosin VIIa, the gene product defective in Usher syndrome type 1B. Proc. Nat. Acad. Sci. USA 92, 9815–9819 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Woods, C., Montcouquiol, M. & Kelley, M.W. Math1 regulates development of the sensory epithelium in the mammalian cochlea. Nat. Neurosci. 7, 1310–1318 (2004).

    Article  CAS  PubMed  Google Scholar 

  10. Greenwood, D.D. Critical bandwidth and the frequency coordinates of the basilar membrane. J. Acoust. Soc. Am. 33, 1344–1356 (1961).

    Article  Google Scholar 

  11. Dallos, P. & Harris, D. Properties of auditory nerve responses in absence of outer hair cells. J. Neurophysiol. 41, 365–383 (1978).

    Article  CAS  PubMed  Google Scholar 

  12. Teas, D.C. & Nielsen, D.W. Interaural attenuation versus frequency for guinea pig and chinchilla CM response. J. Acoust. Soc. Am. 58, 1066–1072 (1975).

    Article  CAS  PubMed  Google Scholar 

  13. Zheng, J.L. & Gao, W.Q. Overexpression of Math1 induces robust production of extra hair cells in postnatal rat inner ears. Nat. Neurosci. 3, 580–586 (2000).

    Article  CAS  PubMed  Google Scholar 

  14. Cotanche, D.A., Messana, E.P. & Ofsie, M.S. Migration of hyaline cells into the chick basilar papilla during severe noise damage. Hear. Res. 91, 148–159 (1995).

    Article  CAS  PubMed  Google Scholar 

  15. Li, H., Liu, H. & Heller, S. Pluripotent stem cells from the adult mouse inner ear. Nat. Med. 9, 1293–1299 (2003).

    Article  CAS  PubMed  Google Scholar 

  16. Turner, C.W., Gantz, B.J., Vidal, C., Behrens, A. & Henry, B.A. Speech recognition in noise for cochlear implant listeners: benefits of residual acoustic hearing. J. Acoust. Soc. Am. 115, 1729–1735 (2004).

    Article  PubMed  Google Scholar 

  17. Ishimoto, S., Kawamoto, K., Kanzaki, S. & Raphael, Y. Gene transfer into supporting cells of the organ of Corti. Hear. Res. 173, 187–197 (2002).

    Article  CAS  PubMed  Google Scholar 

  18. Brough, D.E. et al. Activation of transgene expression by early region 4 is responsible for a high level of persistent transgene expression from adenovirus vectors in vivo. J. Virol. 71, 9206–9213 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Yamasoba, T. & Dolan, D.F. Chronic strychnine administration into the cochlea potentiates permanent threshold shift following noise exposure. Hear. Res. 112, 13–20 (1997).

    Article  CAS  PubMed  Google Scholar 

  20. Davis, H. Principles of electric response audiometry. Ann. Otol. Rhinol. Laryngol. 85 Suppl 28, 1–96 (1976).

    PubMed  Google Scholar 

  21. Raphael, Y. & Altschuler, R.A. Reorganization of cytoskeletal and junctional proteins during cochlear hair cell degeneration. Cell Motil. Cytoskeleton 18, 215–227 (1991).

    Article  CAS  PubMed  Google Scholar 

  22. Raphael, Y. Reorganization of the chick basilar papilla after acoustic trauma. J. Comp. Neurol. 330, 521–532 (1993).

    Article  CAS  PubMed  Google Scholar 

  23. Beyer, L.A. et al. Hair cells in the inner ear of the pirouette and shaker 2 mutant mice. J. Neurocytol. 29, 227–240 (2000).

    Article  CAS  PubMed  Google Scholar 

  24. Yagi, M. et al. Spiral ganglion neurons are protected from degeneration by GDNF gene therapy. J. Assoc. Res. Otolaryngol. 1, 315–325. (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank L.A. Beyer and L.L. Kabara for technical assistance. We thank P.F. Hitchcock and D.M. Martin for discussions and comments on the manuscript. This work was supported by a gift from B. and A. Hirschfield, by GenVec and by US National Institutes of Health–National Institute on Deafness and Other Communication Disorders grants R01 DC01634, DC05401 and P30 DC05188. We thank P.J. Olynyk for graphics work on the cover illustration.

Author information

Authors and Affiliations

  1. Department of Otolaryngology, Kresge Hearing Research Institute, University of Michigan, MSRB 3, Room 9303, 1150 W. Medical Center Drive, Ann Arbor, 48109-0648, Michigan, USA

    Masahiko Izumikawa, Ryosei Minoda, Karen A Abrashkin, Donald L Swiderski, David F Dolan & Yehoash Raphael

  2. Department of Otolaryngology, Kansai Medical University, 10-15 Fumizono-Cho, Moriguchi, 570–8506, Osaka, Japan

    Masahiko Izumikawa & Kohei Kawamoto

  3. Department of Otolaryngology–Head and Neck Surgery, Kumamoto University School of Medicine, 1-1-1 Honjo, Kumamoto, 860–8556, Japan

    Ryosei Minoda

  4. Department of Vector Sciences, GenVec Inc., 65 W. Watkins Mill Road, Gaithersburg, 20879-4021, Maryland, USA

    Douglas E Brough

Authors
  1. Masahiko Izumikawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ryosei Minoda
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kohei Kawamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Karen A Abrashkin
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Donald L Swiderski
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. David F Dolan
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Douglas E Brough
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yehoash Raphael
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yehoash Raphael.

Ethics declarations

Competing interests

D.E. Brough is employed by GenVec. GenVec provided viral vectors and support for this work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Izumikawa, M., Minoda, R., Kawamoto, K. et al. Auditory hair cell replacement and hearing improvement by Atoh1 gene therapy in deaf mammals. Nat Med 11, 271–276 (2005). https://doi.org/10.1038/nm1193

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm1193

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing