Auditory hair cell replacement and hearing improvement by Atoh1 gene therapy in deaf mammals.
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.
Izumikawa
Masahiko
M
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.
Minoda
Ryosei
R
Kawamoto
Kohei
K
Abrashkin
Karen A
KA
Swiderski
Donald L
DL
Dolan
David F
DF
Brough
Douglas E
DE
Raphael
Yehoash
Y
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D003051:Cochlea / Q000473:pathology; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics*; D004976:Ethacrynic Acid; D018507:Gene Expression Regulation, Developmental; D015316:Genetic Therapy / Q000379:methods*; D006168:Guinea Pigs; D006198:Hair Cells, Auditory / Q000254:growth & development / Q000502:physiology*; D006319:Hearing Loss, Sensorineural / Q000139:chemically induced / Q000628:therapy*; D018257:Helix-Loop-Helix Motifs; D007612:Kanamycin; D009416:Nerve Regeneration; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics*; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics*
D004268:DNA-Binding Proteins; D009419:Nerve Tissue Proteins; D014157:Transcription Factors; D007612:Kanamycin; D004976:Ethacrynic Acid