Otolaryngology - Theses
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ItemGene therapy for the preservation and regeneration of spiral ganglion neurons and hair cells after deafness( 2013)Sensorineural hearing loss results from damage to or loss of the sensory hair cells of the cochlea. Currently, the only widely used clinical device to restore hearing is the cochlear implant. The implant functions by bypassing the lost or damaged hair cells and directly stimulates the remaining auditory neurons. However, there is also a secondary degeneration of the auditory neurons, which is thought to be due to the removal of neurotrophin support provided by the hair cells and support cells and electrical activity. The administration of exogenous neurotrophins to the deaf cochlea has been shown to protect the auditory neurons from degeneration and promote resprouting of the peripheral fibres. The duration of the protective effect afforded by neurotrophin treatment, however, has yet to be shown to persist long-term after cessation of treatment, suggesting continuous delivery is necessary. A clinically viable way to deliver neurotrophins long-term, however, has yet to be established. Experimentally, the direct infusion of neurotrophins has also been shown to lead to ectopic and disorganised resprouting of the peripheral fibres, which may have a deleterious effect on cochlear implant efficacy, especially as electrode designs and stimulation strategies become more focused with the aim of stimulating more discrete neuronal populations. The work conducted in this thesis was based on gene therapy techniques to achieve two main goals: the sustained protection of auditory neurons and the regeneration of the sensory hair cells after hearing loss. In both studies viral gene therapy was used, localising the delivery to the scala media of the cochlea to target gene expression to the organ of Corti. The first study aimed to examine whether localised neurotrophin gene therapy could provide sustained support for auditory neurons and enable controlled resprouting of their peripheral fibres. The second main study aimed to determine if the introduction of the transcription factor Atoh1 would regenerate hair cells in the deaf cochlea and lead to functional improvements. In this thesis neurotrophin gene therapy was shown to lead to a significant increase in SGN survival compared to the contralateral non-treated cochlea after aminoglycoside-induced sensorineural hearing loss. Furthermore, the localised introduction of neurotrophins promoted the controlled resprouting of peripheral fibres towards transduced cellular targets. Neurotrophin gene therapy did not, however, prevent the degeneration of the organ of Corti after hearing loss and, as a result the level of gene expression and overall SGN protected was limited after extended periods of time. In the second main study a significantly greater number of HCs was observed after hearing loss in Atoh1 treated cochleae compared to contralateral non-treated cochleae and to cochleae examined after four days post deafening. There was, however, no functional recovery of hearing. The lack of recovery was hypothesised to originate from the small number of hair cells that were present after treatment compared to the normal cochlea and also the lack of connections with the peripheral fibres. Collectively, these studies have demonstrated that neurotrophin gene therapy is able to promote the survival of auditory neurons and the regrowth of peripheral fibres. Moreover, it has been demonstrated that sensory cells of the cochlea can be protected and regenerated after profound hearing loss with Atoh1 gene therapy. With further development of gene therapy techniques and in our understanding of the genes required for mature hair cell development, reconnection of the cochlea and restoration of hearing could be achieved.