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Concept: Organ of Corti


Efforts to develop gene therapies for hearing loss have been hampered by the lack of safe, efficient, and clinically relevant delivery modalities. Here we demonstrate the safety and efficiency of Anc80L65, a rationally designed synthetic vector, for transgene delivery to the mouse cochlea. Ex vivo transduction of mouse organotypic explants identified Anc80L65 from a set of other adeno-associated virus (AAV) vectors as a potent vector for the cochlear cell targets. Round window membrane injection resulted in highly efficient transduction of inner and outer hair cells in mice, a substantial improvement over conventional AAV vectors. Anc80L65 round window injection was well tolerated, as indicated by sensory cell function, hearing and vestibular function, and immunologic parameters. The ability of Anc80L65 to target outer hair cells at high rates, a requirement for restoration of complex auditory function, may enable future gene therapies for hearing and balance disorders.

Concepts: Gene, Genetics, Bacteria, Auditory system, Cochlea, Inner ear, Mouse, Organ of Corti


Meniere’s disease is characterized by sporadic episodes of vertigo, nystagmus, fluctuating sensorineural hearing loss, tinnitus and aural pressure. Since Meniere’s disease can affect different regions of the vestibular labyrinth, we investigated if electrical vestibular stimulation (EVS) which excites the entire vestibular labyrinth may be useful to reveal patchy endorgan pathology. We recorded three-dimensional electrically evoked vestibulo-ocular reflex (eVOR) to transient EVS using bilateral, bipolar 100-ms current steps at intensities of 0.9, 2.5, 5.0, 7.5 and 10.0 mA with dual-search coils in 12 unilateral Meniere’s patients. Their results were compared to 17 normal subjects. Normal eVOR had tonic and phasic spatiotemporal properties best described by the torsional component, which was four times larger than horizontal and vertical components. At EVS onset and offset of 8.9 ms latency, there were phasic eVOR initiation (M = 1,267 °/s(2)) and cessation (M = -1,675 °/s(2)) acceleration pulses, whereas during the constant portion of the EVS, there was a maintained tonic eVOR (M = 9.1 °/s) at 10 mA. However in Meniere’s disease, whilst latency of EVS onset and offset was normal at 9.0 ms, phasic eVOR initiation (M = 1,720 °/s(2)) and cessation (M = -2,523 °/s(2)) were enlarged at 10 mA. The initiation profile was a bimodal response, whilst the cessation profile frequently did not return to baseline. The tonic eVOR (M = 20.5 °/s) exhibited a ramped enhancement of about twice normal at 10 mA. Tonic eVOR enhancement was present for EVS >0.9 mA and disproportionately enhanced the torsional, vertical and horizontal components. These eVOR abnormalities may be a diagnostic indicator of Meniere’s disease and may explain the vertigo attacks in the presence of declining mechanically evoked vestibular responses.

Concepts: Vestibular system, Vestibulo-ocular reflex, Ear, Tinnitus, Ménière's disease, Pathologic nystagmus, Organ of Corti, Endolymph


Sensorineural hearing loss (SNHL) is mainly caused by the damage of cochlear hair cells (HCs). As HCs and supporting cells (SCs) do not proliferate in postnatal mammals, the loss of HCs and SCs is irreversible, emphasizing the importance of preserving their numbers to prevent SNHL. It is known that insulin-like growth factor 1 (IGF1) is instrumental in the treatment of SNHL. Our previous study indicates that IGF1 protects HCs against aminoglycoside by activating IGF1 receptor and its two major downstream pathways, PI3K/AKT and MEK/ERK, in SCs, which results in the upregulation of the expression of the Netrin1-encoding gene (Ntn1). However, the mechanisms underlying IGF1-induced protection of HCs via SC activation as well as the role of NTN1 in this process have not been elucidated. Here, we demonstrated that NTN1, similar to IGF1, promoted HC survival. NTN1 blocking antibody attenuated IGF1-induced HC protection from aminoglycoside, indicating that NTN1 is the effector molecule of IGF1 signaling during HC protection. In situ hybridization demonstrated that IGF1 potently induced Ntn1 expression in SCs. NTN1 receptors were abundantly expressed in the cochlea; among them, UNC5B mediated IGF1 protective effects on HCs, as NTN1 binding to UNC5B inhibited HC apoptosis. These results provide new insights into the mechanisms underlying IGF1 protection of cochlear HCs, suggesting a possibility of using NTN1 as a new treatment for SNHL.

Concepts: Immune system, Hormone, Cochlea, Cochlear implant, Ear, Tinnitus, Sensorineural hearing loss, Organ of Corti


Low-frequency hearing is critically important for speech and music perception, but no mechanical measurements have previously been available from inner ears with intact low-frequency parts. These regions of the cochlea may function in ways different from the extensively studied high-frequency regions, where the sensory outer hair cells produce force that greatly increases the sound-evoked vibrations of the basilar membrane. We used laser interferometry in vitro and optical coherence tomography in vivo to study the low-frequency part of the guinea pig cochlea, and found that sound stimulation caused motion of a minimal portion of the basilar membrane. Outside the region of peak movement, an exponential decline in motion amplitude occurred across the basilar membrane. The moving region had different dependence on stimulus frequency than the vibrations measured near the mechanosensitive stereocilia. This behavior differs substantially from the behavior found in the extensively studied high-frequency regions of the cochlea.

Concepts: Auditory system, Cochlea, Sense, Ear, Inner ear, Sound, Basilar membrane, Organ of Corti


Synapses between cochlear nerve terminals and hair cells are the most vulnerable elements in the inner ear in both noise-induced and age-related hearing loss, and this neuropathy is exacerbated in the absence of efferent feedback from the olivocochlear bundle. If age-related loss is dominated by a lifetime of exposure to environmental sounds, reduction of acoustic drive to the inner ear might improve cochlear preservation throughout life. To test this, we removed the tympanic membrane unilaterally in one group of young adult mice, removed the olivocochlear bundle in another group and compared their cochlear function and innervation to age-matched controls one year later. Results showed that tympanic membrane removal, and the associated threshold elevation, was counterproductive: cochlear efferent innervation was dramatically reduced, especially the lateral olivocochlear terminals to the inner hair cell area, and there was a corresponding reduction in the number of cochlear nerve synapses. This loss led to a decrease in the amplitude of the suprathreshold cochlear neural responses. Similar results were seen in two cases with conductive hearing loss due to chronic otitis media. Outer hair cell death was increased only in ears lacking medial olivocochlear innervation following olivocochlear bundle cuts. Results suggest the novel ideas that 1) the olivocochlear efferent pathway has a dramatic use-dependent plasticity even in the adult ear and 2) a component of the lingering auditory processing disorder seen in humans after persistent middle-ear infections is cochlear in origin.

Concepts: Action potential, Auditory system, Cochlea, Middle ear, Ear, Sound, Hair cell, Organ of Corti


Assessment of the impact of noise over-exposure in stranded cetaceans is challenging, as the lesions that lead to hearing loss occur at the cellular level and inner ear cells are very sensitive to autolysis. Distinguishing ante-mortem pathology from post-mortem change has been a major constraint in diagnosing potential impact. Here, we outline a methodology applicable to the detection of noise-induced hearing loss in stranded cetaceans. Inner ears from two mass strandings of long-finned pilot whales in Scotland were processed for scanning electron microscopy observation. In one case, a juvenile animal, whose ears were fixed within 4 hours of death, revealed that many sensory cells at the apex of the cochlear spiral were missing. In this case, the absence of outer hair cells would be compatible with overexposure to underwater noise, affecting the region which transduces the lowest frequencies of the pilot whales hearing spectrum. Perfusion of cochlea with fixative greatly improved preservation and enabled diagnostic imaging of the organ of Corti, even 30 hours after death. This finding supports adopting a routine protocol to detect the pathological legacy of noise overexposure in mass stranded cetaceans as a key to understanding the complex processes and implications that lie behind such stranding events.

Concepts: Auditory system, Cochlea, Hearing impairment, Ear, Inner ear, Hair cell, Basilar membrane, Organ of Corti


Adeno-associated virus (AAV) is a safe and effective vector for gene therapy for retinal disorders. Gene therapy for hearing disorders is not as advanced, in part because gene delivery to sensory hair cells of the inner ear is inefficient. Although AAV transduces the inner hair cells of the mouse cochlea, outer hair cells remain refractory to transduction. Here, we demonstrate that a vector, exosome-associated AAV (exo-AAV), is a potent carrier of transgenes to all inner ear hair cells. Exo-AAV1-GFP is more efficient than conventional AAV1-GFP, both in mouse cochlear explants in vitro and with direct cochlear injection in vivo. Exo-AAV shows no toxicity in vivo, as assayed by tests of auditory and vestibular function. Finally, exo-AAV1 gene therapy partially rescues hearing in a mouse model of hereditary deafness (lipoma HMGIC fusion partner-like 5/tetraspan membrane protein of hair cell stereocilia [Lhfpl5/Tmhs(-/-)]). Exo-AAV is a powerful gene delivery system for hair cell research and may be useful for gene therapy for deafness.

Concepts: Protein, Gene, Auditory system, Cochlea, Hearing impairment, Inner ear, Hair cell, Organ of Corti


Hearing loss affects more than two-thirds of the elderly population, and more than 17% of all adults in the U.S. Sensorineural hearing loss related to noise exposure or aging is associated with loss of inner ear sensory hair cells (HCs), cochlear spiral ganglion neurons (SGNs), and ribbon synapses between HCs and SGNs, stimulating intense interest in therapies to regenerate synaptic function. 7,8-Dihydroxyflavone (DHF) is a selective and potent agonist of tropomyosin receptor kinase B (TrkB) and protects the neuron from apoptosis. Despite evidence that TrkB agonists can promote survival of SGNs, local delivery of drugs such as DHF to the inner ear remains a challenge. We previously demonstrated in an animal model that a fluorescently labeled bisphosphonate, 6-FAM-Zol, administered to the round window membrane penetrated the membrane and diffused throughout the cochlea. Given their affinity for bone mineral, including cochlear bone, bisphosphonates offer an intriguing modality for targeted delivery of neurotrophic agents to the SGNs to promote survival, neurite outgrowth, and, potentially, regeneration of synapses between HCs and SGNs. The design and synthesis of a bisphosphonate conjugate of DHF (Ris-DHF) is presented, with a preliminary evaluation of its neurotrophic activity. Ris-DHF increases neurite outgrowth in vitro, maintains this ability after binding to hydroxyapatite, and regenerates synapses in kainic acid-damaged cochlear organ of Corti explants dissected in vitro with attached SGNs. The results suggest that bisphosphonate-TrkB agonist conjugates have promise as a novel approach to targeted delivery of drugs to treat sensorineural hearing loss.

Concepts: Auditory system, Cochlea, Cochlear implant, Ear, Sensorineural hearing loss, Inner ear, Hair cell, Organ of Corti


The sensory and supporting cells of the organ of Corti are derived from a limited number of progenitors. The mechanisms that regulate the number of sensory progenitors are not known. Here, we show that Fibroblast Growth Factors (FGF) 9 and 20, which are expressed in the non-sensory (Fgf9) and sensory (Fgf20) epithelium during otic development, regulate the number of cochlear progenitors. We further demonstrate that Fgf receptor (Fgfr) 1 signaling within the developing sensory epithelium is required for the differentiation of outer hair cells and supporting cells, while mesenchymal FGFRs regulate the size of the sensory progenitor population and the overall cochlear length. In addition, ectopic FGFR activation in mesenchyme was sufficient to increase sensory progenitor proliferation and cochlear length. These data define a feedback mechanism, originating from epithelial FGF ligands and mediated through periotic mesenchyme that controls the number of sensory progenitors and the length of the cochlea.

Concepts: Auditory system, Cochlea, Fibroblast growth factor, Sensorineural hearing loss, Hair cell, Organ of Corti, Fibroblast growth factor receptor, Fibroblast growth factor receptor 3


The use of viral vectors for inner ear gene therapy is receiving increased attention for treatment of genetic hearing disorders. Most animal studies to date have injected viral suspensions into neonatal ears, via the round window membrane. Achieving transduction of hair cells, or sensory neurons, throughout the cochlea has proven difficult, and no studies have been able to efficiently transduce sensory cells in adult ears while maintaining normal cochlear function. Here, we show, for the first time, successful transduction of all inner hair cells and the majority of outer hair cells in an adult cochlea via virus injection into the posterior semicircular canal. We used a “designer” AAV, AAV2/Anc80L65, in which the main capsid proteins approximate the ancestral sequence state of AAV1, 2, 8, and 9. Our injections also transduced ~10% of spiral ganglion cells and a much larger fraction of their satellite cells. In the vestibular sensory epithelia, the virus transduced large numbers of hair cells and virtually all the supporting cells, along with close to half of the vestibular ganglion cells. We conclude that this viral vector and this delivery route hold great promise for gene therapy applications in both cochlear and vestibular sense organs.

Concepts: Nervous system, DNA, Auditory system, Cochlea, Vestibular system, Ear, Gene therapy, Organ of Corti