title: Hair cell regeneration after ATOH1 gene therapy in the cochlea of profoundly deaf adult guinea pigs.
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.
authors.affiliation: Bionics Institute, East Melbourne, Victoria, Australia; Department of Otolaryngology, University of Melbourne, East Melbourne, Victoria, Australia.
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Atkinson
authors.affiliation: Bionics Institute, East Melbourne, Victoria, Australia; Department of Otolaryngology, University of Melbourne, East Melbourne, Victoria, Australia; Department of Medical Bionics, University of Melbourne, East Melbourne, Victoria, Australia.
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Wise
authors.affiliation: Bionics Institute, East Melbourne, Victoria, Australia.
authors.forename: Brianna O
authors.initials: BO
authors.lastname: Flynn
authors.affiliation: Bionics Institute, East Melbourne, Victoria, Australia; Department of Otolaryngology, University of Melbourne, East Melbourne, Victoria, Australia; Department of Audiology and Speech Pathology, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Bryony A
authors.initials: BA
authors.lastname: Nayagam
authors.affiliation: Bionics Institute, East Melbourne, Victoria, Australia; Department of Otolaryngology, University of Melbourne, East Melbourne, Victoria, Australia; Department of Medical Bionics, University of Melbourne, East Melbourne, Victoria, Australia.
authors.forename: Rachael T
authors.initials: RT
authors.lastname: Richardson
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics*; D003638:Deafness / Q000235:genetics / Q000473:pathology / Q000503:physiopathology* / Q000628:therapy*; D005260:Female; D015316:Genetic Therapy; D006168:Guinea Pigs; D006198:Hair Cells, Auditory / Q000473:pathology / Q000502:physiology*; D006309:Hearing / Q000235:genetics; D008297:Male; D051379:Mice; D012038:Regeneration / Q000235:genetics*; D013569:Synapses / Q000502:physiology
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; C500943:Atoh1 protein, mouse