Emerging therapies for human hearing loss
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Abstract:
More than 5% of the world's population have a disabling hearing loss which can be managed by hearing aids or implanted electrical devices. However, outcomes are highly variable, and the sound perceived by recipients is far from perfect. Sparked by the discovery of progenitor cells in the cochlea and rapid progress in drug delivery to the cochlea, biological and pharmaceutical therapies are currently in development to improve the function of the cochlear implant or eliminate the need for it altogether.This review highlights progress in emerging regenerative strategies to restore hearing and adjunct therapies to augment the cochlear implant. Novel approaches include the reprogramming of progenitor cells to restore the sensory hair cell population in the cochlea, gene therapy, and gene editing to treat hereditary and acquired hearing loss. A detailed review of optogenetics is also presented as a technique that could enable optical stimulation of the spiral ganglion neurons, replacing or complementing electrical stimulation.Increasing evidence of substantial reversal of hearing loss in animal models, alongside rapid advances in delivery strategies to the cochlea and learnings from clinical trials will amalgamate into a biological or pharmaceutical therapy to replace or complement the cochlear implant.Keywords:
Spiral ganglion
Regenerative Medicine
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Objective To reveal cystathionine-γ-lyase (CSE) expression pattern and localization in the adult rat cochlea and their changes following noise exposure. Methods An immunohistochemistry method was used to detect expression of CSE in the cochlea tissue in 32 adult Sprague Dawley (SD) rats without noise exposure and at.1 day, 1 week or 3 weeks after exposure to white noise at 110 dB SPL. Differences in CSE expressions with and without noise exposure were examined using RT-PCR. Results CSE was expressed in the stria vascularis, spiral ligaments, microvascular and vascular endothelium of the modiolar artery, but not in the organ of Corti and spiral ganglion cells. The expression level of CSE mRNA increased at 1 day and 1 week following noise exposure, but decreased at 3 weeks. Conclusion These findings suggest that CSE is expressed in the normal rat cochlea, and its reduced expression after noise exposure may be related to regulation of cochlear blood flow.
Spiral ganglion
Spiral ligament
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In mammals, the size and number of spiral ganglion cells can vary significantly along the length of the cochlea. At present, it is unclear how these topologic differences in spiral ganglion cell morphology and density emerge during development. We addressed this issue by quantifying developmental changes in the number, density, and size of auditory ganglion cells within the cochlea of Mongolian gerbils throughout the first 3 weeks of postnatal life. In each cochlea, cells were measured at five standardized locations along the length of the spiral ganglion, as determined from serial reconstruction of Rosenthal's canal. During the first postnatal week, the total number of gerbil spiral ganglion cells decreased significantly by 27%, without further change thereafter. This brief period of neuronal cell death coincides with a major remodeling in the afferent neural projections to gerbil auditory hair cells (Echteler [1992] Proc. Natl. Acad. Sci. USA 89:6324-6327). The resulting reduction in neuronal density varied with location, being most prominent within the upper basal and lower middle turns of the cochlea. These same regions contained the smallest auditory ganglion cells found within the gerbil ear and exhibited the least amount of developmental expansion in the circumference of Rosenthal's canal. These results suggest the possibility that regional differences in auditory neuron size and number might be influenced by local extrinsic factors, such as the availability of canal space.
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For patients
suffering from sensorineural hearing loss due to damaged hair cells of the
cochlea, a cochlear implant can restore auditory function. It electrically
stimulates the spiral ganglion neurons of the auditory nerve, bypassing the
no longer functioning hair cells. However, hearing performance is strongly
dependent on the ambient conditions. In noisy environments, especially the
capability to understand speech deteriorates significantly. This has been
partially attributed to the low spatial precision of the electric stimulation
since the electric field extends over a large area in tissue. Due to the
tonotopy of the cochlea, low spatial specificity corresponds to low frequency
selectivity.
In contrast, laser light can stimulate tissue very site-specific promising
higher frequency selectivity and thus an improved hearing performance.
Therefore, the optical stimulation of the cochlea was investigated in the
last years in a number of in vivo experiments. Although the feasibility of
the optical stimulation of the cochlea was demonstrated, the stimulation
mechanism is still unclear. Although they could provide insight into the
mechanism of optical stimulation of the cochlea, in vitro studies concerning
the reaction of spiral ganglion neurons to irradiation over a broad
wavelength range are yet not available.
Therefore, in this study single cell measurements on spiral ganglion neurons
and model cells, which were irradiated over a wavelength range of 420 nm
to 1950 nm with laser pulses of 5 ns duration, were performed using
the patch clamp technique. It could be demonstrated that irradiation with
laser light produces similar electrophysiological responses in different cell
types. The laser-induced inward current responses at resting potential were
linearly dependent on the pulse energy of the laser light and the absorption
coefficient of water. The observed cell responses are consistent with the
assumption that they are based on a common underlying mechanism which relies
on a change in the capacitance of the cell membrane generated by a
laser-induced temperature change or a laser-induced pressure pulse.
Furthermore, for spiral ganglion neurons it could be shown that optical
stimulation resulted in a slight depolarization which was not sufficient to
generate action potentials. Since in this investigation much higher radiant
exposures were used than in comparable in vivo studies, the results indicate
that in a stimulation paradigm with nanosecond-pulses, direct stimulation of
spiral ganglion neurons is not the main cause of optical cochlea stimulation.
The results rather support the theory that the optical stimulation of the
cochlea is based on an optoacoustic effect for the investigated laser
parameters. Thus, the absorption of the laser pulse in the cochlea would lead
to the generation of pressure waves that finally stimulate the still intact
inner hair cells. Therefore, an optical cochlear implant may substitute
damaged outer hair cells, respectively their frequency selective gain, but
requires, similar to conventional hearing aids, the presence of inner hair
cells.
Spiral ganglion
Tonotopy
Modiolus (cochlea)
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Objective To determine the expression of inducible nitric oxide synthase (iNOS) in cochlea of the aged guinea pigs. Methods Twenty guinea pigs were divided into two groups: experimental group(33 35 months old) and control group(2 3 months old). The threshold of auditory brain stem response (ABR) of two groups was measured, iNOS was examined in the cochlea of both groups using immunohistochemical method. Results The ABR threshold of coantor group was (22 0±5 3) dBspL, and the experimental group was (50 0±10 5) dBspL, There was a significant difference in ABR threshold between two groups ( P 0 05).The iNOS was expressed in stria vascularis and spiral ganglion cell of the cochlea of experimental group, and was not expressed in the control group. Conclusions The expression of iNOS was positive in the cochlea of the aged guinea pigs. It suggests that nitric oxide (NO) takes a very important role in the aging process of cochleas of guinea pigs.
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Spiral ligament
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Hypothesis: Different members of the Nogo system are expressed in the mammalian cochlea. Background: The protein Nogo has gained a lot of attention during the last couple of years because it inhibits neurite outgrowth in the adult central nervous system. In contrast to the central nervous system, very little is known regarding the expression and possible function of the Nogo system within the inner ear. Methods: Using reverse-transcriptase-polymerase chain reaction and immunohistochemistry, we analyzed for the expression of members of the Nogo system within the cochlea. In addition, we determined hearing levels of Nogo A knockout and wild-type mice with auditory brainstem response audiometry. Results: In this study, we demonstrate the expression of Nogo A, B, C, and of Nogo receptor mRNA in the organ of Corti, spiral ganglion, and stria vascularis. Immunohistochemistry revealed that Nogo A and Nogo receptor localize to the spiral ganglion neurons. Interestingly, Nogo A expression was also observed in the outer and inner hair cells of the organ of Corti. As revealed by light microscopy, deletion of Nogo A does not alter cochlear microanatomy. We have assessed hearing levels in 10-month old wild-type and Nogo A knockout mice, and thereby, we could not detect any differences between these 2 groups. Conclusion: Different members of the Nogo family are expressed in the mammalian cochlea. Deletion of Nogo A does not alter cochlea microanatomy or hearing levels compared with wild-type mice.
Spiral ganglion
Knockout mouse
Neurite
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Lots of adrenergic receptors (ARs) are widely present across the auditory pathways and are positioned to affect auditory and vestibular functions. However, noradrenergic regulation in the cochlea has not been well characterized. In this study, a rat model of noise-induced hearing loss was developed to investigate the expression of α2A-adrenergic receptor (AR) after acoustic trauma, then, we investigated the expression of α2A-AR in the developing rat cochlea using immunofluorescence, qRT-PCR, and Western blotting. We found that the expression of α2A-AR significantly increased in rats exposed to noise compared with controls. Immunofluorescence analysis demonstrated that α2A-AR is localized on hair cells (HCs), spiral ganglion neurons (SGNs), and the stria vascularis (SV) in the postnatal developing cochlea from post-natal day (P) 0 to P28. Furthermore, we observed α2A-AR mRNA reached a maximum level at P14 and P28 when compared with P0, while no significant differences in α2A-AR protein levels at the various stages when compared with P0. This study provides direct evidence for the expression of α2A-AR in HCs, SGNs, and the SV of the cochlea, indicating that norepinephrine might play a vital role in hearing function within the cochlea through α2A-AR.
Spiral ganglion
Immunofluorescence
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Spiral ganglion
Gerbil
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Objective To detect the expression of caspase-3 in the cochlea of old aged guinea pigs.Methods Guinea pigs of the experimental group were 33 to 35 months old,and those of the control group were 2 to 3 months old.Caspase-3 was detected in the cochlea of both groups with the method of immunohistochemistry.Results The expression of caspase-3 was positive in the cochlea of experimental guinea pigs,and the caspase-3 positive area was in spiral ganglion cells,while caspase-3 was negative in the control group.Conclusion The expression of caspase-3 was positive in the spiral ganglion cellsof aged guinea pig,which suggests that caspase-3 plays a very important part in the process of aging of the guinea pig's cochlea.
Spiral ganglion
Caspase 8
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Effects of exposure to acute hypoxia on expression of heat shock protein 90 in cochlea of guinea pig
To investigate the expression of heat shock protein 90(HSP 90) in cochlea of guinea pig after exposure to acute hypoxia. Methods: The animals were put in the hypoxic gas chamber for 1 h and then their cochlea were taken out. The expression of HSP 90 in cochlea of these animals was examined by immunohistochemistry and image analysis system. Results: In both normal group and hypoxic group, the HSP 90 was stained in cochlea, but the expression of HSP 90 was significantly enhanced after hypoxic exposure, especially in spiral ganglion, organ of Corti, stria vascularis and spiral ligament . The enhancement of expression of HSP 90 was more obvious at organ of Corti and stria vascularis in hypoxic group than those in normal group. Conclusion: HSP 90 is expressed in cochlea of normal and hypoxic guinea pigs and hypoxia is of an obvious revulsive effect on the expression of HSP 90 in cochlea.
Spiral ganglion
Spiral ligament
Hypoxia
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