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Objective: To evaluate the effect of transtympanic administration of tumor necrosis factor α (TNF-α) blockers to patients suffering from autoimmune inner ear disease (AIED). Study Design: Nonrandomized, prospective pilot study. Setting: Tertiary referral center. Patients: 9 patients (4 men and 5 women; aged 51.22 ± 13.11 years) presenting with autoimmune sensorineural hearing loss who responded to oral steroid treatment. Two groups of patients were treated. Group A consisted of 5 patients with AIED who could not be tapered off steroids. Group B consisted of 4 patients who were treated with intratympanic anti-TNF-α antibody therapy alone after a relapse of hearing loss following discontinuation of steroids. Intervention: A Silverstein MicroWickTM local delivery system was placed in the round window niche and the patients were treated for 4 weeks with a weekly infusion of infliximab, a monoclonal antibody against TNF-α. Main Outcome Measure(s): Evaluation of hearing thresholds at 250–8000 Hz was performed before and after implantation of the Silverstein MicroWick and local delivery of the TNF-α blocker. Results: Local administration of the TNF-α blocker allowed methylprednisolone to be tapered off without loss of hearing function in 4/5 steroid-dependent patients. Four additional patients were treated only with anti-TNF-α perfusion to the round window membrane without concomitant systemic administration of methylprednisolone. In 3 of these 4 patients, the pure tone average improved to 22.6 ± 15.7 dB, resulting in hearing recovery comparable to treatment with systemic methylprednisolone. The 7 responding patients showed a significant reduction of recurrence of hearing loss to 0.028 ± 0.072 episodes per month over the 4.3 ± 2.4 months of the post-treatment period compared to 0.84 ± 0.4 recurrences per week seen in the pretreatment period. Conclusions: The results of this pilot trial demonstrate that in patients with AIED, transtympanic delivery of the TNF-α blocker infliximab once weekly for 4 weeks allowed steroids to be tapered off, resulted in hearing improvement and reduced disease relapses. These preliminary efficacy and safety results appear encouraging enough to warrant further follow-up and studies for better determination of the potential clinical utility of local administration of infliximab for autoimmune hearing loss. Copyright © 2006 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

The aim of this study was to determine if high-dose delivery of methylprednisolone to the round window can improve hearing after the failure of conventional treatment for sudden sensorineural hearing loss (SSHL). In 6 patients with SSHL an Intraear microcatheter was placed in the round window niche and methylprednisolone (62.5 mg/ml) was infused at a rate of 10 microl/h for 8-10 days. Audiometric assessments (including measurement of speech discrimination) were made at presentation, either every day or every other day during treatment and 5 days after the completion of perfusion. Perfusion of methylprednisolone was beneficial for all 6 patients, with a 16.25-25 dB improvement in hearing threshold. A dramatic improvement in speech discrimination was also noted in all patients. In conclusion, methylprednisolone perfused at the level of the round window membrane resulted in significant recovery of hearing function after the failure of standard treatment of SSHL. [ABSTRACT FROM AUTHOR]

Autoimmune inner ear disease is a treatable cause of sensorineural hearing loss and it is important for physicians and hearing health professionals to recognize that early diagnosis and proper management strategies may result in stabilization and improvement in hearing. The pathogenesis of autoimmune sensorineural hearing loss remains unclear but antibodies directed against the inner ear and/or cellular effectors have been proposed. Therefore, immunosuppressive drugs such as steroids and methotrexate are administered to interfere with the progression of hearing loss and in some cases have been found to improve hearing. We report herein the history of a patient who was treated by systemic administration of anti-tumor necrosis factor-alpha antibodies for Crohn's disease and who also had associated sensorineural hearing loss. Audiometric follow-up revealed not only the efficacy of tumor necrosis factor-alpha blockade in arresting the hearing loss but also an improvement in hearing of 15 dB on average across all frequencies. Hearing remained stable afterwards. [ABSTRACT FROM AUTHOR]

Autoimmune inner ear disease is a treatable cause of sensorineural hearing loss and it is important for physicians and hearing health professionals to recognize that early diagnosis and proper management strategies may result in stabilization and improvement in hearing. The pathogenesis of autoimmune sensorineural hearing loss remains unclear but antibodies directed against the inner ear and/or cellular effectors have been proposed. Therefore, immunosuppressive drugs such as steroids and methotrexate are administered to interfere with the progression of hearing loss and in some cases have been found to improve hearing. We report herein the history of a patient who was treated by systemic administration of anti-tumor necrosis factor-α antibodies for Crohn's disease and who also had associated sensorineural hearing loss. Audiometric follow-up revealed not only the efficacy of tumor necrosis factor-α blockade in arresting the hearing loss but also an improvement in hearing of 15 dB on average across all frequencies. Hearing remained stable afterwards. [ABSTRACT FROM AUTHOR]

The last several years have seen the first human trials of inner ear gene therapy and cell therapy launching a range of therapeutic interventions that we will need to incorporate into cochlear implant practice. We will review the rationale for generating human auditory hair cells and the implications of molecular therapeutics for cochlear implantation. We will discuss how to choose patients for high-risk clinical trials, review the clinical safety data from current trials and discuss means to optimize gene delivery into the inner ear. Challenges in moving therapy for forward include identifying the molecular and cellular causes of hearing loss, identifying optimal times for delivery of medications to the cochlea and most importantly managing the patient's expectations of outcomes. The next 10 years should show continued improvement and refinement of cochlear implant technology and the beginnings of hybrid device/molecular therapeutic interventions. Hearing preservation cochlear implantation in particular presents the opportunity to potentially improve low-frequency hearing, thereby improving EAS outcomes, as well as identifying patients with progressive ski slope hearing losses whose progressive hearing loss could be halted through gene therapy and their high-frequency hearing rehabilitated through electrical stimulation. These ideas will be further discussed in the subsequent panel. [ABSTRACT FROM AUTHOR]

Hearing loss (HL) affects approximately 20% of the global population and the treatments are currently limited to hearing aids and cochlea implants. Gene therapy offers a possibility to prevent or even cure HL. With the aim to optimize the adeno-associated virus (AAV) vector system for inner ear directed gene therapy, we generated AAV peptide display libraries based on the AAV1, AAV2 and AAV6 capsid backbones. All libraries present random unique 7-mer peptide inserts at variable region VIII of the capsid protein with diversities ranging from 80,000-622,000 (maximum likelihood estimate, MLE). We conducted high-throughput in vivo selection screens in the inner ear of adult mice, testing alternative administration routes that demand overcoming robust biological barriers. The target tissue is the organ of Corti with its crucial mechanosensory hair cells (HCs) of the inner ear, the supporting cells (SCs) and the underlying spiral ganglion neurones (SGNs). Distinct variants were found to be accumulated to up to 5% for AAV2-based variants and up to 2.5% for AAVl-derived capsids after two rounds of in vivo selection. Interestingly, some top variants were already accumulated for the AAV6 KO library after only one selection round. A total of 20 top candidates from the AAV1 and AAV2 libraries were produced as vectors. They outperform the parental serotypes and show diverse expression patterns in the adult mouse cochlea. Three promising variants had the ability to transduce outer HCs, a challenging cell type to infect, and many also targeted inner HCs. Almost half of the variants also strongly transduced all layers of the stria vascula-ris - a viable target tissue for the treatment of age-related HL - and the SGNs were targeted, with 4 variants being highly specific for SGNs. In addition, different intensities of fluorescent transgene expression suggest differential efficacy in delivery or vector uncoating within the cells of the inner ear. Thus, we report on a set of promising new AAV variants with distinct features developed by in vivo high throughput selection screens for improving inner ear directed gene therapy. [ABSTRACT FROM AUTHOR]

Introduction: Cochlear implantation induces trauma leading to immunological reactions compromising the performance of the implant. Vesicle-enriched secretome fractions (VSF) derived from human umbilical cord mesenchymal stromal cells is a new class of biological therapeutic targeting cochlear cells to modulate immunological processes. Previously, efficacy in spiral ganglion cell culture and attenuation of threshold shifts and protection of hair cells in vivo were shown. Safety, biodistribution and neuroprotective effects of VSF to maintain gross structural integrity of the cochlea after implantation trauma has been evaluated. Material and methods: Hearing guinea pigs (GP) were implanted with a cochlear implant followed by administration of VSF and hearing was assessed until sacrifice after 4 weeks. A long-term group of hearing GP received VSF with a six month follow up of monthly hearing measurement. A third group of hearing GP received labelled VSF investigating distribution of VSF in the inner ear 1-2 hours post application. All groups underwent detailed histological assessment. Results: Treatment with VSF improved hearing after cochlear implantation compared to control animals. Fibrosis 4 weeks post implantation was at similar level to control animals. Electrophysiological and histological findings of the long-term group revealed no adverse effects of VSF and ABR thresholds remained on a similar level compared to control. Positive fluorescent signal of labelled VSF was confirmed in cells of the inner ear. Conclusions: Uptake of labelled VSF into the guinea pig cochlea has been demonstrated and treatment with VSF seems to mediate immunological processes to a healthier state and maintain gross structural integrity. Application of VSF associated with cochlear implantation seems to be a safe and solid combination to prevent post implantation trauma and preserve residual hearing. This work was funded by Med-El, the Deutsche Forschungs-gemeinschaft (DFG, German Research Foundation) under Germany's Excellence Strategy - EXC 2177/1 - Project ID 390895286 and by the European Regional Development Fund Interreg V-A Italia-Austria 2014-2020 (Project "EXOTHERA IT AT 1036") and the Project "ExtraNeu" from the State of Salzburg. [ABSTRACT FROM AUTHOR]

Background: One of the most significant recent advances in cochlear implantation is the implantation of patients with residual hearing. These patients have a downsloping sensorineural hearing loss with poor speech discrimination and perform poorly with standard amplification. Studies using a variety of different electrode designs have demonstrated that it is possible to implant an inner ear and preserve residual hearing. Initial studies have demonstrated that a combination of residual acoustic hearing in the low frequencies with electrical stimulation in the mid- to high frequencies resulted in superior hearing performance in background noise. Purpose: The objective of this study was to determine the effect of electrode insertion depth on hearing preservation. Study Sample: Eighteen patients with mild to severe hearing loss in the low frequencies combined with poor word recognition were recruited for the study. Intervention: Cochlear implantation. Data Collection and Analysis: Pre- and postoperative hearing test, Hearing in Noise Test, and consonant-nucleus-consonant testing. Data analysis was performed with Kruskal Wallis and Mann-Whitney testing. Results: In our study of 18 patients implanted with a Med-El PulsarCI100 we demonstrated the ability to preserve residual hearing with implant insertion depths ranging from 20 to 28 mm, giving us the possibility of near complete cochlear frequency coverage with an implant array while preserving residual hearing. These patients performed well both in quiet and in 10 dB signal-to-noise ratio conditions. Conclusion: Hearing preservation was achievable even with deep implant insertion. Patients performed well in combined acoustic and electric conditions. [ABSTRACT FROM AUTHOR]

Hearing loss (HL) affects over 460 million people worldwide, significantly affecting quality of life. Genetic analysis has identified more than 150 causative monogenic genes for non-syndromic sensorineural hearing loss, presenting attractive targets for gene therapy interventions. These approaches also have the potential to enhance conventional treatment strategies. Particularly interesting in this regard are cochlear implants (CI), used for severe to profound HL. However, their efficacy is believed to depend on spiral ganglion neuron (SGN) survival. Recognizing the potential of neurotrophins to enhance SGN survival and improve CI outcomes, we here report on the development of a novel adeno-associated virus (AAV) vector optimized for transducing SGN, even in adult mice and at low vector doses. For this purpose, the capsid was engineered to display a heptamer peptide, which was previously derived from a phage library screen. Structure-focused modeling of our novel vector Var9 indicated a clear change in cell attachment receptor binding due to peptide insertion compared to its parental serotype AAV2. Predictions were confirmed using affinity chromatography and competition assays. Interestingly, Var9 demonstrated faster transgene expression in HEI-OC1 cells, a murine otic progenitor cell line, despite significantly lower entry efficiency, indicating enhanced intracellular processing of the vector. Subsequent IF-FISH analysis at single-cell level as well as our indirect uncoating assay revealed that Var9 vectors clearly outperform AAV2 vectors regarding kinetics and level of uncoating (3-fold), i.e. release of their genome from the capsid, a prerequisite for transgene transcription. Finally, in a neurotrophic gene therapy approach, Var9 effectively prevented SGN degeneration by overexpressing BDNF in SGN of deafened mice. Histological analysis of the cochlea revealed remarkable protective effects of SGN comparable to untreated control levels in all cochlear turns of mice treated with Var9-BDNF. In conclusion, our novel AAV vector demonstrated superior properties crucial for efficient SGN transduction and will be further refined for clinical applications, aiming to enhance neural survival and improve outcomes for cochlear gene therapy in CI recipients. [ABSTRACT FROM AUTHOR]

Loss of balance is often due to loss of vestibular hair cells. In mammals, regeneration of functional hair cells in the mature sensory epithelium is limited; therefore, loss of sensory cells can lead to debilitating balance problems. Delivery of the transcription factor atonal (atoh1) after aminoglycoside ototoxicity has previously been shown to induce the transdifferentiation of supporting cells into new hair cells and restore function. A problem with mouse aminoglycoside models is that the partial loss of hair cells seen in human disease is difficult to establish consistently. To more closely mirror human clinical balance dysfunction, we have used systemic application of 3,3′-iminodipropionitrile (IDPN), a vestibulotoxic nitrile compound known to cause vestibular hair cell loss, to induce a consistent partial loss of vestibular hair cells. To determine if balance function could be restored, we delivered atoh1 using a new adenovirus vector, based on Ad28. The Ad28 adenovector is based on a human serotype with a low seroprevalence that appears to target gene delivery to vestibular supporting cells. To further provide cell type selectivity of gene delivery, we expressed atoh1 using the supporting cell-specific glial fibrillary acid protein promoter. Delivery of this vector to IDPN-damaged vestibular organs resulted in a significant recovery of vestibular hair cells and restoration of balance, as measured by time on rotarod compared with untreated controls. [ABSTRACT FROM AUTHOR]

MRI scans are widely utilized in medicine for the diagnosis of a broad range of disorders throughout the body. With the prevalence of MRI use, it is almost certain that cochlear implant patients will receive an MRI scan at some time during their life. Different implant companies have significantly different protocols for performing MRI scans on patients with cochlear implants. Options for some devices include magnet removal, wrapping the head over the implant tightly, and for newer generation MedEl devices, scanning the patient without any additional interventions. The variation in devices both by manufacturer and generation of cochlear implant make it difficult for radiology teams to determine the optimal protocol when scanning patients, especially in environments where the imaging center is not associated with an established implant center. This potentially leads to complications such as magnet displacement and pain during the MRI scan and additional costs due to rescheduled or incomplete imaging. Our cochlear implant clinic in partnership with radiologists have developed protocols to ensure patients' device is properly identified and prepared for safe MRI scans. These protocols also allow device identification and communication with remote radiology locations. Importantly, implant teams should discuss the current state of MRI compatibility with patients to ensure that these factors are taking into account when choosing a device. We will discuss work flows that we have developed to improve management of MRI scanning in patients with cochlear implants. [ABSTRACT FROM AUTHOR]

Objectives: Hearing implants amplify or restore hearing in individuals with different severities of hearing loss. Clinical outcome measures usually assess speech understanding in quiet and in noise. In recent years, an increased focus has been placed on hearing implant users' subjective assessment of the benefit that they feel that they derive from device use. This study compares the patient-reported quality of life and quality of hearing before hearing implant activation with that at 6 and 12 months after activation. Material and Methods: The Health Utility Index (HUI) and the Speech, Spatial and Qualities of Hearing Scale (SSQ12) were administered to individuals who received a cochlear implant (CI), BoneBridge, or VIBRANT SoundBridge. The Nijmegen Cochlear Implant Questionnaire (NCIQ) was only completed by the CI subjects. The questionnaires were administered at all three intervals (before first activation and after 6 and 12 months after first activation). Additionally, the subjects' satisfaction with their audio processors was recorded at the 6 and 12-month intervals using the Audio Processor Satisfaction Questionnaire (APSQ). Results: Preliminary data analyses of 85 CI recipients and 36 VIBRANT recipients showed that quality of life and quality of hearing increased from pre-activation level to the 6-month interval in all measures. The SSQ total scores improved significantly for both the CI (p < .001) and the VIBRANT subjects (p = .009). From the HUI2 and HUI3 data, the multi-attribute scores were calculated and a "clinically important improvement" was found for both CI and VIBRANT subjects. The NCIQ scores (CI subjects only) improved significantly from the baseline visit to the 6-month interval for all 6 subscales (all p < .05). Further, the descriptive analysis of the APSQ revealed a generally highly level of satisfaction with their audio processors (median score of 4.1 for CI subjects and 4.2 for VIBRANT subjects with 5 being the max. score). Conclusions: The present data show that hearing implant users feel that their quality of life and quality of hearing both significantly benefit from hearing implant use. Overall, these results suggest the importance of hearing implant provision on users' lives beyond simply an increase in speech understanding. [ABSTRACT FROM AUTHOR]

The article focuses on the aspects of heating preservation classification. It states that the classification is needed due to the increasing number of patients with cochlear implant who have preserved hearing. It says that many efforts for the hearing preservation identification after the implantation of cochlear have been limited to a group of subjects. It adds that the proposed classification requires various factors such as initial hearing, cochlear patient and ease of use classification.