Nature Medicine11, 271 - 276 (2005)
Published online: 13 February 2005; | doi:10.1038/nm1193
Auditory hair cell replacement and hearing improvement by Atoh1 gene therapy in deaf mammals
Masahiko Izumikawa1, 2, Ryosei Minoda1, 3, Kohei Kawamoto2, Karen A Abrashkin1, Donald L Swiderski1, David F Dolan1, Douglas E Brough4
& Yehoash Raphael1
1
Kresge Hearing Research Institute, Department of Otolaryngology, University of Michigan, MSRB 3, Room 9303, 1150 W. Medical Center Drive, Ann Arbor, Michigan 48109-0648, USA.
2
Department of Otolaryngology, Kansai Medical University, 10-15 Fumizono-Cho, Moriguchi, Osaka 570−8506, Japan.
3
Department of Otolaryngology−Head and Neck Surgery, Kumamoto University School of Medicine, 1-1-1 Honjo, Kumamoto 860−8556, Japan.
4
Department of Vector Sciences, GenVec Inc., 65 W. Watkins Mill Road, Gaithersburg, Maryland 20879-4021, USA.
Correspondence should be addressed to Yehoash Raphael yoash@umich.edu
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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