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Title: The effect of deafness duration on neurotrophin gene therapy for spiral ganglion neuron protection
Authors: Wise, Andrew
Tu, Tian
Atkinson, Patrick
Flynn, Brianna
Sgro, Beatrice
Hume, Cliff
O'Leary, Stephen
Shepherd, Robert
Richardson, Rachael
Keywords: Adenoviridae - Genetics
Brain-Derived Neurotrophic Factor - Genetics
Brain-Derived Neurotrophic Factor - Therapeutic use
Cell Count
Cell Survival
Deafness - Pathology
Deafness - Physiopathology
Deafness - Therapy
Gene Expression
Genes, Reporter
Genetic Therapy - Methods
Genetic Vectors
Nerve Growth Factors - Genetics
Nerve Growth Factors - Therapeutic use
Neurons - Pathology
Neurotrophin 3 - Genetics
Neurotrophin 3 - Therapeutic use
Recombinant Proteins - Genetics
Recombinant Proteins - Therapeutic use
Spiral Ganglion - Innervation
Spiral Ganglion - Pathology
Spiral Ganglion - Physiopathology
Time Factors
Issue Date: Aug-2011
Publisher: Elsevier
Citation: Wise, A. K., Tu, T., Atkinson, P. J., Flynn, B. O., Sgro, B. E., Hume, C., O'Leary, S. J., Shepherd, R. K., & Richardson, R. T. (2011). The effect of deafness duration on neurotrophin gene therapy for spiral ganglion neuron protection. Hearing Research, 278(1-2), 69-76.
Abstract: A cochlear implant can restore hearing function by electrically exciting spiral ganglion neurons (SGNs) in the deaf cochlea. However, following deafness SGNs undergo progressive degeneration ultimately leading to their death. One significant cause of SGN degeneration is the loss of neurotrophic support that is normally provided by cells within the organ of Corti (OC). The administration of exogenous neurotrophins (NTs) can protect SGNs from degeneration but the effects are short-lived once the source of NTs has been exhausted. NT gene therapy, whereby cells within the cochlea are transfected with genes enabling them to produce NTs, is one strategy for providing a cellular source of NTs that may provide long-term support for SGNs. As the SGNs normally innervate sensory cells within the OC, targeting residual OC cells for gene therapy in the deaf cochlea may provide a source of NTs for SGN protection and targeted regrowth of their peripheral fibers. However, the continual degeneration of the OC over extended periods of deafness may deplete the cellular targets for NT gene therapy and hence limit the effectiveness of this method in preventing SGN loss. This study examined the effects of deafness duration on the efficacy of NT gene therapy in preventing SGN loss in guinea pigs that were systemically deafened with aminoglycosides. Adenoviral vectors containing green fluorescent protein (GFP) with or without genes for Brain Derived Neurotrophic Factor (BDNF) and Neurotrophin-3 (NT3) were injected into the scala media (SM) compartment of cochleae that had been deafened for one, four or eight weeks prior to the viral injection. The results showed that viral transfection of cells within the SM was still possible even after severe degeneration of the OC. Supporting cells (pillar and Deiters' cells), cells within the stria vascularis, the spiral ligament, endosteal cells lining the scala compartments and interdental cells in the spiral limbus were transfected. However, the level of transfection was remarkably lower following longer durations of deafness. There was a significant increase in SGN survival in the entire basal turn for cochleae that received NT gene therapy compared to the untreated contralateral control cochleae for the one week deaf group. In the four week deaf group significant SGN survival was observed in the lower basal turn only. There was no increase in SGN survival for the eight week deaf group in any cochlear region. These findings indicated that the efficacy of NT gene therapy diminished with increasing durations of deafness leading to reduced benefits in terms of SGN protection. Clinically, there remains a window of opportunity in which NT gene therapy can provide ongoing trophic support for SGNs.
URI: http://repository.bionicsinstitute.org:8080/handle/123456789/38
ISSN: 1878-5891
Appears in Collections:Bionic Hearing Research Publications

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