Atoh1 induces auditory hair cell recovery in mice after ototoxic injury

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Abstract
Objectives/Hypothesis: To evaluate the ability of the Ad28.gfap.atoh1 to promote hair cell regeneration and hearing recovery in cochlea injured with kanamycin and furosemide.Study Design: In vivo model of hair cell ablation and subsequent treatment with Atoh1.Methods: The hair cells of C57BL/6 mice were ablated with systemic administration of kanamycin and furosemide. The left ears were treated with Ad28.gfap.atoh1. The right ears were not treated. Preablation audiograms and distortion product otoacoustic emissions (DPOAEs) were compared to 1‐ or 2‐month postablation studies. Harvested cochleae were examined for histologic evidence of hair cell regeneration and spiral ganglion cell survival.Results: Delivery of Ad28.gfap.atoh1 results in development of auditory hair cells. There was no recovery of DPOAEs at 1 or 2 months post‐treatment. Two months after delivery of Ad28.gfap.atoh1, the left ear exhibited a moderate recovery of hearing at 4 and 8 kHz (P < .01). There was no significant difference at 16 or 32 kHz. One month after treatment, myosin VII‐positive immunohistochemical staining can be seen in both the inner and outer hair cells of the treated ear. In the untreated ear, minimal myosin VII‐positive debris is seen, with no indication of normal hair cells. Two months after ablation, there is evidence of hair cell recovery on the treated side, whereas the untreated cochlea demonstrates a flattened epithelium. Untreated ears showed decreased spiral ganglion cell density at the basal turn compared to treated ears.Conclusions: Ad28.gfap.atoh1 promotes hair cell regeneration in cochlea ablated with kanamycin and furosemide resulting in moderate hearing recovery.

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