Article

Auditory hair cell replacement and hearing improvement by Atoh1 gene therapy in deaf mammals. Nature Medicine, 11(3), 271-276

Kumamoto University, Kumamoto, Kumamoto, Japan
Nature Medicine (Impact Factor: 28.05). 04/2005; 11(3):271-6. DOI: 10.1038/nm1193
Source: PubMed

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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Available from: Douglas E Brough, Aug 29, 2015
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    • "In the mammalian cochlea, researchers have identified stem cell-like cells (Li et al., 2003; Oshima et al., 2007; Taniguchi et al., 2012; Jan et al., 2013). The functional restoration of mammalian cochleae was achieved via several challenging strategies in experimental animals (Izumikawa et al., 2005; Okano et al., 2005; Chen et al., 2012; Mizutari et al., 2013; Tona et al., 2014a). However, the quality of functionality of the regenerated cochleae is not satisfactory. "
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    ABSTRACT: Sensorineural hearing loss (SNHL) is a common disability in the world; however, at present, options for the pharmacological treatment of SNHL are very limited. Previous studies involving human temporal bone analyses have revealed that the degeneration of the cochlea is a common mechanism of SNHL. A major problem for the development of novel pharmacotherapy for SNHL has been the limited regeneration capacity in mammalian cochlear cells. However, recent progress in basic studies has led to several effective strategies for the induction of regeneration in the mammalian cochlea, in accordance with the stage of degeneration. In addition, recent advances in the identification of human deafness genes and their characterization in mouse models have elucidated cellular and/or molecular mechanisms of SNHL, which will contribute to clarify molecular targets of pharmacotherapy for treatment of SNHL.
    Frontiers in Pharmacology 09/2014; 5:206. DOI:10.3389/fphar.2014.00206 · 3.80 Impact Factor
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    • "Experimental manipulations reintroducing ATOH1 into the deaf cochlea has also highlighted the role of this transcription factor in HC development. An initial study in the short-term (four day) ototoxically deafened guinea pig (GP), demonstrated both a greater number of HCs in the viral-mediated ATOH1-treated cochlea (as noted by the expression of a known HC marker, myosinVIIa) and also a significant improvement in hearing thresholds (as measured by auditory brainstem responses; ABRs) [10]. These results in the mature GP provided evidence that it is possible to manipulate non-sensory cells to generate sensory HCs, which subsequently leads to improved auditory function. "
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    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.
    PLoS ONE 07/2014; 9(7):e102077. DOI:10.1371/journal.pone.0102077 · 3.23 Impact Factor
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    • "These findings suggest that induction of hair cells from supporting cells contributed to hair cell preservation in MDL-treated cochleae. However, direct evidence for trans-differentiation of supporting cells into hair cells, which was shown in previous studies [18,20], was not demonstrated in the present study. MDL is also known as a calpain inhibitor. "
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    ABSTRACT: Background Notch signaling plays a crucial role in the fate determination of cochlear progenitor cells, hair cells, and supporting cells in the developing cochlea. Recent studies have demonstrated the temporal activation of Notch signaling in damaged mature cochleae, and have demonstrated the induction of new hair cells by pharmacologically inhibiting Notch signaling. The present study aimed to illustrate the feasibility of pharmacologically inhibiting Notch signaling by using a gamma-secretase inhibitor for treating sensorineural hearing loss. Results The effect of the sustained local delivery of MDL28170, a gamma-secretase inhibitor, on hearing and hair cell induction was tested in a guinea pig model with noise-induced hearing loss. MDL28170 was directly delivered into the cochlear fluids via a micro-osmotic pump. Drug application was initiated 7 days after noise exposure. Measurements of auditory brainstem responses revealed better hearing in the MDL28170-treated animals than in the vehicle controls. Histological analysis demonstrated a higher number of outer hair cells in the MDL28170-treated cochleae than the vehicle-treated cochleae. Conclusion These findings strongly suggest that local sustained delivery of a gamma-secretase inhibitor into the cochlea could be a novel strategy for treating acute hearing loss that is refractory to conventional treatment.
    BMC Neuroscience 05/2014; 15(1):66. DOI:10.1186/1471-2202-15-66 · 2.85 Impact Factor
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