Hair Cell Regeneration after ATOH1 Gene Therapy in the Cochlea of Profoundly Deaf Adult Guinea Pigs
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Date
2014-07-18
Journal Title
Journal ISSN
Volume Title
Publisher
PLoS ONE
Abstract
The degeneration of hair cells in the mammalian cochlea results in permanent sensorineural hearing loss. This study aimed
to promote the regeneration of sensory hair cells in the mature cochlea and their reconnection with auditory neurons
through the introduction of ATOH1, a transcription factor known to be necessary for hair cell development, and the
introduction of neurotrophic factors. Adenoviral vectors containing ATOH1 alone, or with neurotrophin-3 and brain derived
neurotrophic factor were injected into the lower basal scala media of guinea pig cochleae four days post ototoxic
deafening. Guinea pigs treated with ATOH1 gene therapy, alone, had a significantly greater number of cells expressing hair
cell markers compared to the contralateral non-treated cochlea when examined 3 weeks post-treatment. This increase,
however, did not result in a commensurate improvement in hearing thresholds, nor was there an increase in synaptic
ribbons, as measured by CtBP2 puncta after ATOH1 treatment alone, or when combined with neurotrophins. However, hair
cell formation and synaptogenesis after co-treatment with ATOH1 and neurotrophic factors remain inconclusive as viral
transduction was reduced due to the halving of viral titres when the samples were combined. Collectively, these data
suggest that, whilst ATOH1 alone can drive non-sensory cells towards an immature sensory hair cell phenotype in the
mature cochlea, this does not result in functional improvements after aminoglycoside-induced deafness.
Description
Keywords
Hair Cell Regeneration, Gene Therapy, ATOH1, Profound Deafness
Citation
2. Atkinson, P. J., Wise, A. K., Flynn, B. O., Nayagam, B. A. & Richardson, R. T. (2014). Hair cell regeneration after ATOH1 gene therapy in the cochlea of profoundly deaf adult guinea pigs. PLoS ONE 9, e102077.