Therapeutic potential of a gamma-secretase inhibitor for hearing restoration in a guinea pig model with noise-induced hearing loss

Abstract

BackgroundNotch 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.ResultsThe 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.ConclusionThese 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.

Manipulating cell fate in the cochlea: a feasible therapy for hearing loss

“…The result demonstrated the successful transdifferentiation of supporting cells to hair cells that were functional (38). Similar findings were recently reported by Tona et al (41). …”

“…Transdifferentiation approaches have now been tested with small molecules with the goal of future clinical use (38, 41). We successfully induced hair cells using LY411575, a potent γ-secretase inhibitor (Fig.…”

Development of the inner ear

“…Nevertheless, various approaches may be able to overcome this problem. Following on from promising work using Notch inhibitors in embryonic or neonatal systems, two studies have shown that localised treatment with inhibitors of Notch signalling can rescue both outer hair cell number (via direct transdifferentiation of supporting cells) and some limited hearing function in the noise-damaged mature mammalian cochlea [49,50]. Indeed, the importance of Notch signalling in the regenerative process has been underlined by a comprehensive transcriptome analysis of the regenerating chick utricle [51].…”

Sensory hair cell development and regeneration: similarities and differences

“…Building on these findings, two recent studies examined the damaged neonatal mouse cochlea and demonstrated a similar ability of supporting cells to regenerate nascent hair cells after Notch inhibition (Bramhall et al, 2014;Korrapati et al, 2013). This pharmacological approach has also been applied to the damaged, mature mammalian cochlea, but yielded a significantly less robust regenerative response (Mizutari et al, 2013;Tona et al, 2014); unlike the effects observed in the zebrafish lateral line system and chick cochlea, the regenerated hair cells were attributed to direct transdifferentiation of supporting cells, as no cell proliferation was found. Although it is commonly postulated that the regeneration of a functional organ of Corti requires the coordination of supporting cell proliferation and hair cell differentiation such that a balanced ratio of sensory and non-sensory cell types is maintained, a modest functional improvement was observed using this pharmacological approach (Mizutari et al, 2013).…”