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

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.

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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.

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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.

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Correspondence to Yehoash Raphael.

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

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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

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