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Sensorineural hearing loss (SNHL) is the most common sensory deficit worldwide. Due to the heterogeneity of causes for SNHL, effective treatment options remain scarce, creating an unmet need for novel drugs in the field of otology. Cochlear implantation (CI) currently is the only established method to restore hearing function in profound SNHL and deaf patients. The cochlear implant bypasses the non-functioning sensory hair cells (HCs) and electrically stimulates the neurons of the cochlear nerve. CI also benefits patients with residual hearing by combined electrical and auditory stimulation. However, the insertion of an electrode array into the cochlea induces an inflammatory response, characterized by the expression of pro-inflammatory cytokines, upregulation of reactive oxygen species, and apoptosis and necrosis of HCs, putting residual hearing at risk. Here, we characterize the small molecule AC102, a pyridoindole, for its protective effects on residual hearing in CI. In a gerbil animal model of CI, AC102 significantly improves the recovery of hearing thresholds across multiple frequencies and confines the cochlear trauma to the directly mechanically injured area. In addition, AC102 significantly preserves auditory nerve fibers and inner HC synapses throughout the whole cochlea. In vitro experiments in an ethanol challenged HT22 cell-line revealed significant and dose-responsive anti-apoptotic effects following the treatment of with AC102. Further, AC102 treatment resulted in significant downregulation of the expression of pro-inflammatory cytokines in an organotypic ex vivo model of electrode insertion trauma (EIT). These results suggest that AC102's effects are likely elicited during the inflammatory phase of EIT and mediated by anti-apoptotic and anti-inflammatory properties, highlighting AC102 as a promising compound for hearing preservation during CI. Moreover, since the inflammatory response in CI shares similarities to that in other etiologies of SNHL, AC102 may be inferred as a potential general treatment option for various inner ear conditions., (© 2024. The Author(s).)

Introduction: Even with recent research advances, effective delivery of a compound to its target cells inside the inner ear remains a challenging endeavor due to anatomical and physiological barriers. Direct intracochlear drug administration with an inner ear catheter (IEC) aims to overcome this obstacle and strives to provide a safe and efficient way for inner ear pharmacotherapy. The goal of this study was to histologically and audiologically evaluate the traumatic properties of a novel IEC for intracochlear drug delivery in a large animal model., Methods: Seven inner ears of piglets that had undergone intracochlear fluorescein isothiocyanate dextran application via an IEC ( n  = 4) or round window membrane (RWM) puncture with a needle ( n  = 3) followed by sequential apical perilymph sampling were histologically analyzed. Additionally, obtained objective auditory compound action potential and cochlear microphonic measurements were compared. Cochlear cryosections were stained using hematoxylin and eosin, and preservation of inner ear structures was investigated. Moreover, one cochlea was methylmethacrylate-embedded and analyzed with the IEC in situ ., Results: Histological evaluation revealed an atraumatic insertion and subsequent compound application in a majority of IEC-inserted inner ears. Click cochlear compound action potential (CAP) shifts in the IEC groups reached a maximum of 5 dB (1.25 ± 2.5 dB) post administration and prior to perilymph sampling. In comparison, application by RWM puncture generated a maximum click CAP hearing threshold shift of 50 dB (23.3 ± 23.1 dB) coinciding with coagulated blood in the basal cochlear turn in one specimen of the latter group. Furthermore, in situ histology showed an atraumatic insertion of the IEC demonstrating preserved intracochlear structures., Conclusion: The IEC appears to be a promising and efficient way for inner ear drug delivery. The similarities between the porcine and human inner ear enhance the clinical translation of our findings and increase confidence regarding the safe applicability of the IEC in human subjects., Competing Interests: CA receives research funding from MED-EL. LL receives research funding from Decibel Therapeutics/Regeneron Pharmaceuticals and Amgen and has worked as an independent consultant for Gerson Lehrman Group and Conclave Capital. The funders were not involved in the study design, collection, analysis, interpretation of data, the writing of this article, or the decision to submit it for publication. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Gerlitz, Yildiz, Gadenstaetter, Niisuke, Kandathil, Nieratschker, Landegger, Honeder and Arnoldner.)

Hearing impairment is the most common sensory disorder in humans, and yet hardly any medications are licensed for the treatment of inner ear pathologies. Intricate pharmacokinetic examinations to better understand drug distribution within this complex organ could facilitate the development of novel therapeutics. For such translational research projects, animal models are indispensable, but differences in inner ear dimensions and other anatomical features complicate the transfer of experimental results to the clinic. The gap between rodents and humans may be bridged using larger animal models such as non-human primates. However, their use is challenging and impeded by administrative, regulatory, and financial hurdles. Other large animal models with more human-like inner ear dimensions are scarce. In this study, we analyzed the inner ears of piglets as a potential representative model for the human inner ear and established a surgical approach for intracochlear drug application and subsequent apical sampling. Further, controlled intracochlear delivery of fluorescein isothiocyanate-dextran (FITC-d) was carried out after the insertion of a novel, clinically applicable CE-marked cochlear catheter through the round window membrane. Two, six, and 24 hours after a single injection with this device, the intracochlear FITC-d distribution was determined in sequential perilymph samples. The fluorometrically assessed concentrations two hours after injection were compared to the FITC-d content in control groups, which either had been injected with a simple needle puncture through the round window membrane or the cochlear catheter in combination with a stapes vent hole. Our findings demonstrate not only significantly increased apical FITC-d concentrations when using the cochlear catheter but also higher total concentrations in all perilymph samples. Additionally, the concentration decreased after six and 24 hours and showed a more homogenous distribution compared to shorter observation times., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Yildiz, Gadenstaetter, Gerlitz, Landegger, Liepins, Nieratschker, Glueckert, Staecker, Honeder and Arnoldner.)