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Concept: Cochlea

170

Domestic dogs can suffer from hearing losses that can have profound impacts on working ability and quality of life. We have identified a type of adult-onset hearing loss in Border Collies that appears to have a genetic cause, with an earlier age of onset (3-5 years) than typically expected for aging dogs (8-10 years). Studying this complex trait within pure breeds of dog may greatly increase our ability to identify genomic regions associated with risk of hearing impairment in dogs and in humans. We performed a genome-wide association study (GWAS) to detect loci underlying adult-onset deafness in a sample of 20 affected and 28 control Border Collies. We identified a region on canine chromosome 6 that demonstrates extended support for association surrounding SNP Chr6.25819273 (p-value = 1.09×10(-13)). To further localize disease-associated variants, targeted next-generation sequencing (NGS) of one affected and two unaffected dogs was performed. Through additional validation based on targeted genotyping of additional cases (n = 23 total) and controls (n = 101 total) and an independent replication cohort of 16 cases and 265 controls, we identified variants in USP31 that were strongly associated with adult-onset deafness in Border Collies, suggesting the involvement of the NF-κB pathway. We found additional support for involvement of RBBP6, which is critical for cochlear development. These findings highlight the utility of GWAS-guided fine-mapping of genetic loci using targeted NGS to study hereditary disorders of the domestic dog that may be analogous to human disorders.

Concepts: Genetics, Cochlea, Hearing impairment, Genome-wide association study, Audiogram, Dog, Dog breed, Dog health

169

To test the influence of multiple factors on cochlear implant (CI) speech performance in quiet and in noise for postlinguistically deaf adults, and to design a model of predicted auditory performance with a CI as a function of the significant factors.

Concepts: Cochlea, Hearing impairment, Cochlear implant, Implants, Otology, Models of deafness

167

A topographical representation for frequency has been identified throughout the auditory brain in animals but with limited evidence in humans. Using a midbrain implant, we identified an ordering of pitch percepts for electrical stimulation of sites across the human inferior colliculus (IC) that was consistent with the IC tonotopy shown in animals. Low pitches were perceived by the subject for stimulation of superficial IC sites while higher pitches were perceived for stimulation of deeper sites. Interestingly, this pitch ordering was not initially observed for stimulation across the IC, possibly due to central changes caused by prior hearing loss. Daily implant stimulation for about 4 months altered the pitch percepts from being predominantly low to exhibiting the expected ordering across the stimulated IC. A presumably normal tonotopic representation may have been maintained within the IC or accessible through IC stimulation that helped form this pitch ordering perceived in higher centers.

Concepts: Nervous system, Psychology, Neuroanatomy, Brain, Human brain, Cerebral cortex, Cochlea, Sense

167

To evaluate the onset of vertigo, hearing loss and tinnitus in Ménière’s disease and the associated endolymphatic hydrops (EH) of the inner ear.

Concepts: Auditory system, Cochlea, Hearing impairment, Ear, Tinnitus, Ménière's disease, Inner ear, Endolymph

147

Background Rates of hearing preservation following surgery via middle fossa craniotomy in patients harboring tumors with unfavorable characteristics are significantly lower than for those patients with “favorable” tumors. Objectives We will present two cases both with unfavorable conditions, which underwent endoscopic-assisted middle fossa craniotomy (MFC) resection of intracanalicular vestibular schwannomas with preserved postoperative hearing. Methods Chart reviews were conducted on both patients. Their presentation, intraoperative details, and techniques, pre- and postoperative audiograms, and facial nerve outcomes are presented. Results Patient A had 5.6 × 6.8 × 13.2 mm intracanalicular tumor with unserviceable hearing (pure tone audiometry [PTA], 41; speech determination score [SDS], 47%; class D) but was blind so hearing preservation was attempted. Postoperative hearing was preserved (PTA, 47; SDS, 60%; class B). Patient B had a 5 mm round intracanalicular tumor immediately adjacent to the vestibule and cochlea without any fundal fluid present. Preoperative audiogram showed serviceable hearing (PTA, 48; SDS, 88%; class B). Postoperatively, aidable hearing was preserved (PTA, 51; SDS, 76%; class C). Conclusion Hearing preservation surgery via MFC can be enhanced with endoscopic-assisted dissection, especially in the lateral internal auditory canal. The superior optical view allows for preservation of cochlear nerve function and removal of residual tumor not otherwise seen on microscopy.

Concepts: Auditory system, Cochlea, Cranial nerves, Audiogram, Pure tone audiometry, Vestibular schwannoma, Schwannoma, Internal auditory meatus

126

Death of cochlear hair cells, which do not regenerate, is a cause of hearing loss in a high percentage of the population. Currently, no approach exists to obtain large numbers of cochlear hair cells. Here, using a small-molecule approach, we show significant expansion (>2,000-fold) of cochlear supporting cells expressing and maintaining Lgr5, an epithelial stem cell marker, in response to stimulation of Wnt signaling by a GSK3β inhibitor and transcriptional activation by a histone deacetylase inhibitor. The Lgr5-expressing cells differentiate into hair cells in high yield. From a single mouse cochlea, we obtained over 11,500 hair cells, compared to less than 200 in the absence of induction. The newly generated hair cells have bundles and molecular machinery for transduction, synapse formation, and specialized hair cell activity. Targeting supporting cells capable of proliferation and cochlear hair cell replacement could lead to the discovery of hearing loss treatments.

Concepts: DNA, Gene, Histone deacetylase, Stem cell, Auditory system, Cochlea, Hearing impairment, Hair cell

84

Mutation of the Gap Junction Beta 2 gene (GJB2) encoding connexin 26 (CX26) is the most frequent cause of hereditary deafness worldwide and accounts for up to 50% of non-syndromic sensorineural hearing loss cases in some populations. Therefore, cochlear CX26-gap junction plaque (GJP)-forming cells such as cochlear supporting cells are thought to be the most important therapeutic target for the treatment of hereditary deafness. The differentiation of pluripotent stem cells into cochlear CX26-GJP-forming cells has not been reported. Here, we detail the development of a novel strategy to differentiate induced pluripotent stem cells into functional CX26-GJP-forming cells that exhibit spontaneous ATP- and hemichannel-mediated Ca(2+) transients typical of the developing cochlea. Furthermore, these cells from CX26-deficient mice recapitulated the drastic disruption of GJPs, the primary pathology of GJB2-related hearing loss. These in vitro models should be useful for establishing inner-ear cell therapies and drug screening that target GJB2-related hearing loss.

Concepts: DNA, Developmental biology, Stem cell, Cochlea, Hearing impairment, Cochlear implant, Otology, Tinnitus

49

Dietary supplements consisting of beta-carotene (precursor to vitamin A), vitamins C and E and the mineral magnesium (ACEMg) can be beneficial for reducing hearing loss due to aminoglycosides and overstimulation. This regimen also slowed progression of deafness for a boy with GJB2 (CONNEXIN 26) mutations. To assess the potential for treating GJB2 and other forms of hereditary hearing loss with ACEMg, we tested the influence of ACEMg on the cochlea and hearing of mouse models for two human mutations: GJB2, the leading cause of childhood deafness, and DIAPH3, a cause of auditory neuropathy. One group of mice modeling GJB2 (Gjb2-CKO) received ACEMg diet starting shortly after they were weaned (4 weeks) until 16 weeks of age. Another group of Gjb2-CKO mice received ACEMg in utero and after weaning. The ACEMg diet was given to mice modeling DIAPH3 (Diap3-Tg) after weaning (4 weeks) until 12 weeks of age. Control groups received food pellets without the ACEMg supplement. Hearing thresholds measured by auditory brainstem response were significantly better for Gjb2-CKO mice fed ACEMg than for the control diet group. In contrast, Diap3-Tg mice displayed worse thresholds than controls. These results indicate that ACEMg supplementation can influence the progression of genetic hearing loss.

Concepts: Vitamin, Dietary supplement, Cochlea, Hearing impairment, Cochlear implant, Audiogram, Hearing

44

Hearing loss due to damage to auditory hair cells is normally irreversible because mammalian hair cells do not regenerate. Here, we show that new hair cells can be induced and can cause partial recovery of hearing in ears damaged by noise trauma, when Notch signaling is inhibited by a γ-secretase inhibitor selected for potency in stimulating hair cell differentiation from inner ear stem cells in vitro. Hair cell generation resulted from an increase in the level of bHLH transcription factor Atoh1 in response to inhibition of Notch signaling. In vivo prospective labeling of Sox2-expressing cells with a Cre-lox system unambiguously demonstrated that hair cell generation resulted from transdifferentiation of supporting cells. Manipulating cell fate of cochlear sensory cells in vivo by pharmacological inhibition of Notch signaling is thus a potential therapeutic approach to the treatment of deafness. VIDEO ABSTRACT:

Concepts: DNA, Gene expression, Developmental biology, Auditory system, Cochlea, Hearing impairment, Ear, Hair cell

42

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