NF2-related schwannomatosis (NF2-SWN) is a debilitating condition, characterized by bilateral vestibular schwannomas (VSs) that progressively cause irreversible sensorineural hearing loss. Current management relies on surgery or radiotherapy, while bevacizumab (αVEGF) is used off-label, with variable and often transient efficacy. Effective therapies that durably suppress tumor growth and preserve hearing are urgently needed. Although immune checkpoint inhibitors have transformed cancer treatment, their efficacy in non-malignant tumors such as VS remains unclear. Here, we evaluate combined anti-PD1 (αPD1) and αVEGF therapy in two syngeneic, immune-competent VS models. Combination treatment significantly outperforms either monotherapy, inhibiting tumor growth and preventing hearing loss. Mechanistically, αVEGF enhances αPD1 efficacy by normalizing tumor vasculature, improving drug delivery and immune cell infiltration, and promoting cytotoxicity of T and NK cells via NKG2D upregulation. Combined treatment effectively controls tumor growth that progresses despite anti-VEGF therapy. These findings support αPD1 and αVEGF combination therapy as a promising strategy for NF2-SWN.

Rationale: NF2-related schwannomatosis (NF2-SWN) is a progressive neurological disorder with a hallmark of bilateral vestibular schwannomas (VSs), leading to irreversible hearing loss and reduced quality of life. To date, the FDA has not approved any pharmacological therapies for treating VS or hearing loss. While radiotherapy (RT) is the standard treatment for growing VSs, it often exacerbates hearing loss. Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment; however, their efficacy in non-malignant tumors like VS remains largely unexamined. Methods: We used immune-competent VS mouse models to assess the efficacy of combined anti-PD1 (αPD1) and RT treatment, tumor growth, and hearing preservation. Results: We found three significant therapeutic benefits: i) RT induces immunogenic cell death and activates the STING pathway, enhancing αPD1 efficacy and generating long-term immune memory, ii) The combination strategy reduces the required RT dose necessary for effective tumor control, potentially minimizing RT injury to surrounding normal tissues, and iii) RT to peripheral nerve tumor induces a systemic abscopal effect, which enhances αPD-1 efficacy to effectively control intracranial schwannomas without direct irradiation, sparing the cochlea from radiation exposure and avoiding auditory radiation injury. Conclusion: Our findings provide a compelling rationale for deploying ICIs in combination with radiotherapy as a novel treatment approach for patients with VS and NF2-SWN.

BACKGROUND:Hereditary hearing loss is one of the most common disabling disorders in children and lacks effective pharmacological treatments. Recent breakthroughs in OTOF gene therapy clinical trials necessitate standardized frameworks to guide emerging therapies. This study aims to establish the first international consensus on the clinical application of gene therapy for hereditary hearing loss. METHODS:A modified Delphi process was conducted from March 2024 to March 2025, involving 46 multidisciplinary experts from several countries across otology, genetics, audiology, gene therapy, and hearing rehabilitation. After a systematic literature review, as well as integration of research and clinical expertise and experience, three iterative voting rounds (two anonymous surveys and one online consensus meeting) were performed. Statements required ≥75% agreement for inclusion. FINDINGS:From 9,093 publications, 69 were used to draft and support the consensus statements. A total of 30 statements relevant to six domains achieved consensus on gene therapy for hereditary hearing loss, including ethical review (1 statement), patient selection criteria (12 statements), diagnosis and preoperative evaluation (9 statements), gene therapy drug delivery (4 statements), follow-up (3 statements), and post-treatment auditory and speech rehabilitation (1 statement). CONCLUSIONS:This consensus provides the first globally endorsed framework for gene therapy in hereditary hearing loss. It standardizes clinical trial design and patient management, accelerating translation from research to practice while ensuring safety. The guidelines are immediately applicable to OTOF-related hearing loss and adaptable to other genetic forms. FUNDING:This work was supported by the National Natural Science Foundation of China, the German Research Foundation (DFG) via the Cluster of Excellence, and others.

Recent evidence provides strong support for the safe and effective use of gene therapy in humans with hearing loss. By means of a single local injection of a set of adeno-associated virus (AAV) vectors, hearing was partially restored in several children with neurosensory nonsyndromic autosomal recessive deafness 9 (DFNB9), harboring variants in the OTOF gene. Current research focuses on refining endoscopic and transmastoid injection procedures to reduce risks of side effects, as emerging evidence suggests bidirectional fluid exchanges between the ear and the brain. Moreover, gene editing approaches and novel AAV capsids are successfully tested in animal models and will likely lead to enhanced targeting of the cochlea. Here, we cover the recent advances in cochlear gene therapy, provide an overview of the translational potential of these new approaches for existing and future clinical trials, and highlight the translational implications that remain to be determined for their application in humans.

OBJECTIVE:Excessively prescribed opioids promote chronic drug abuse and worsen a highly prevalent public health problem in the era of the opioid epidemic. This study aimed to (a) determine general analgesic prescription patterns after surgery for vestibular schwannoma (VS) with a focus on opioid prescription rates, (b) identify risk factors for receiving narcotics for postoperative pain management, and (c) highlight the feasibility of opioid-free analgesic treatment strategies. STUDY DESIGN:Retrospective chart review. SETTING:Tertiary referral center. PATIENTS:A total of 105 adult inpatients who underwent VS surgery. INTERVENTIONS:Analgesic prescription patterns were evaluated, and factors associated with opioid prescriptions were identified. MAIN OUTCOME MEASURE:Number of prescribed analgesics. RESULTS:Metamizole (=dipyrone) and acetaminophen (=paracetamol) were the most frequently prescribed non-opioid drugs. Sixty-three (60%) patients received an opioid with a median intake of 23.2 ± 24 mg of oral morphine equivalents. Only 10 (9.5%) individuals received opioids for longer than postoperative day 1. Subjects with small tumors undergoing middle cranial fossa tumor removal (p = 0.007) were more likely to receive opioid drugs. In contrast, patients undergoing retrosigmoid craniotomy required fewer opioids for pain control (p = 0.004). Furthermore, individuals receiving opioids were prone to obtain higher dosages of acetaminophen (odds ratio 1.054, 95% confidence interval 1.01-1.10, p = 0.022). CONCLUSIONS:Opioids for acute postoperative analgesia after VS surgery may be necessary in many patients. However, middle- and long-term pain control can be accomplished using non-opioid treatment regimens, resulting in a reduction in opioid prescriptions and the accompanying negative effects on individual and public health.

Hearing loss represents a highly prevalent and debilitating sensory disorder affecting roughly one in five people worldwide. In a majority of patients with congenital hearing loss, genetic mutations cause the disease. Up until recently, therapeutic options for individuals with hearing loss were limited to hearing aids and different types of auditory implants. However, after numerous years of intensive basic and translational research, gene therapy strategies are now being investigated in clinical trials. First results show significant hearing improvement in treated patients, highlighting gene therapy’s role as a promising treatment for certain forms of genetic hearing loss. In this article, we provide an overview of genetic hearing loss and inner ear gene therapy research including relevant strategies that have been established in animal models and will likely be investigated in human patients soon. Furthermore, we summarize and contextualize the novel findings of recently completed and ongoing clinical trials, and discuss future hurdles needed to be overcome to allow for a broad and safe clinical application of inner ear gene therapy.

Objective:To analyze medical device reports (MDR) submitted to the Food and Drug Administration's (FDA) Manufacturer and User Device Facility Experience (MAUDE) database to identify adverse events (AEs) in patients implanted with novel active bone conduction hearing implants (BCIs). Methods:We conducted a search of the FDA MAUDE database on the newest generation of BCIs. Data were collected concerning device malfunctions, patient injuries, factors triggering these incidents, and the subsequent actions taken. Results:In total, 93 (16.7%) device malfunctions and 465 (83.3%) patient injuries with 358 subsequent interventions were identified, resulting in 558 AEs. Although the absolute AE number per device cannot be identified, the following trends were detected: Among the 494 AEs associated with OSI200, 55 (11.1%) reported device malfunctions and 454 (88.9%) cited patient injuries. Out of the 64 AEs linked to BCI602, 28 (59.4%) were associated with malfunctions, whereas 26 (40.6%) involved patient injuries. The most frequently reported particular AEs for the OSI200 were infection (n = 171, 34.6%), extrusion of the device (n = 107, 21.7%), and pain (n = 51, 10.3%). Conversely, no device output (n = 20, 31.3%) and loss of osseointegration (n = 7, 10.9%) were the most reported AEs for the BCI602. Various AEs led to 214 explanations and 77 revision surgeries. Sixty-seven AEs reported conservative treatment. Conclusion:The current study provides an overview of the most commonly reported complications with new active BCIs. Although providing an overview, given the limitations of the FDA MAUDE database, our results have to be interpreted with caution. Level of Evidence:4.

Introduction The minipig represents a highly relevant animal model in translational research. Thus, we used cochlear implants that are typically utilized in a clinical setting for human patients in said porcine inner ears in vivo. To observe and characterize long-term sequelae after electrode insertion, we performed electrocochleography (ECochG) measurements before and after cochlear implantation surgery.

Introduction Currently, glucocorticoids are commonly used as treatment for a multitude of inner ear disorders. Large animal models with human-like inner ear dimensions can provide valuable insights into intracochlear pharmacokinetics, deepening our understanding of how drugs propagate within the cochlea. In a translational research approach, we topically applied dexamethasone (DEX) to the middle and inner ears of piglets and analyzed its distribution in the porcine cochlea.

NF2-related schwannomatosis (NF2-SWN) is a progressive and disabling disease requiring effective treatments. The hallmark of NF2-SWN is bilateral vestibular schwannomas (VSs), which progressively enlarge, leading to permanent sensorineural hearing loss and severely impacting patients' quality of life. Currently, there are no FDA-approved drugs for VS or the associated hearing loss. Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment, but have not yet been systematically investigated in non-malignant tumors such as VS. In our studies, we demonstrated that combining anti-PD1 (aPD1) treatment with radiation therapy (RT) provides three significant therapeutic benefits: i) Enhanced aPD1 efficacy and immune memory: RT induces immunogenic cell death and activates the STING pathway, enhancing aPD1 efficacy and generating long-term immune memory, ii) Reduced RT dose and associated tissue injury: The combination strategy reduces the required RT dose necessary for effective tumor control, potentially minimizing RT injury to surrounding normal tissues, and iii) Elicited abscopal effects on cerebellopontine angle (CPA) schwannomas: RT to peripheral nerve tumor induces a systemic abscopal effect, which synergizes with aPD-1 to effectively control intracranial schwannomas without direct irradiation, sparing the cochlea from radiation exposure and avoiding auditory radiation injury. Together, our findings provide a compelling rationale for deploying ICIs in combination with radiotherapy as a novel treatment approach for patients with VS and NF2-SWN. ### Competing Interest Statement The authors have declared no competing interest.

IntroductionEven 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.MethodsSeven 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.ResultsHistological 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.ConclusionThe 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.

Background: NF2-related schwannomatosis (NF2-SWN) is a debilitating condition that calls for robust treatment options. The defining feature of NF2-SWN is the presence of bilateral vestibular schwannomas (VSs), which grow over time and can result in irreversible sensorineural hearing loss, significantly affecting the quality of life for those affected. At present, there are no FDA-approved medications specifically for treating VS or related hearing loss. VS management involves radiotherapy or surgical resection, while bevacizumab, an anti-vascular endothelial growth factor (VEGF) monoclonal antibody (aVEGF) may be used off-label in NF2-SWN to shrink the tumor. However, not all patients respond, and the effect is not always durable. There is a critical need for effective medications that can stop the growth of VS and prevent hearing loss associated with these tumors. While immune checkpoint inhibitors have transformed cancer therapy, their potential has not been thoroughly explored in non-malignant tumors such as VS. Methods: We characterize the effects of anti-PD1 (aPD1) treatment on tumor growth and hearing function in two syngeneic, immune-competent VS models. Results: We demonstrated that combining aVEGF treatment with aPD1 significantly enhances the efficacy of each monotherapy. Specifically, i) aVEGF enhances aPD1 efficacy by normalizing the tumor vasculature to improve drug delivery and immune cell infiltration, and by activating T cell and NK cell anti-tumor cytotoxicity via NKG2D upregulation; and ii) combining aPD1 with aVEGF treatment effectively controls tumors that progressed despite aVEGF treatment. Conclusion: These findings provide a strong foundation for the development of aPD1 with aVEGF combination therapies for patients with NF2-SWN. ### Competing Interest Statement The authors have declared no competing interest.

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.

ObjectiveDetermining the concentration of prestin in human blood, cerebrospinal fluid (CSF), and perilymph (PL), and evaluating its suitability as a clinical biomarker for sensori-neural hearing loss (SNHL).Study DesignHuman blood, CSF, and PL samples were intraoperatively collected from 42 patients with tumors of the internal auditory canal or with intracochlear tumors undergoing translabyrinthine or middle fossa tumor removal. Prestin concentration was measured using enzyme-linked immunosorbent assay and linear regression analyses were performed to investigate its associations with audiological as well as vestibular test results.SettingTertiary referral center.ResultsThe median prestin concentration in blood samples of the 42 study participants (26 women, mean +/- standard deviation age, 52.7 +/- 12.5 years) was 1.32 (interquartile range, IQR, 0.71-1.99) ng/mL. CSF prestin levels were significantly higher with 4.73 (IQR, 2.45-14.03) ng/mL (P = .005). With 84.74 (IQR, 38.95-122.00) ng/mL, PL prestin concentration was significantly higher compared to blood (P = .01) and CSF (P = .03) levels. Linear regression analyses showed significant associations of CSF prestin concentration with preoperative hearing levels (pure-tone average and word recognition; P = .008, R2 = 0.1894; P = .03, R2 = 0.1857), but no correlations with blood or PL levels.Conclusion and RelevanceThis study's findings highlight the volatile nature of prestin levels and provide the first insights into this potential biomarker's concentrations in body fluids apart from blood. Future investigations should comprehensively assess human prestin levels with different etiologies of SNHL, prestin's natural homeostasis and systemic circulation, and its temporal dynamics after cochlear trauma. Finally, clinically approved detection kits for prestin are urgently required prior to considering a potential translational implementation of this diagnostic technique.

Our sense of hearing is mediated by cochlear hair cells, localized within the sensory epithelium called the organ of Corti. There are two types of hair cells in the cochlea, which are organized in one row of inner hair cells and three rows of outer hair cells. Each cochlea contains a few thousands of hair cells, and their survival is essential for our perception of sound because they are terminally differentiated and do not regenerate after insult. It is often desirable in hearing research to quantify the number of hair cells within cochlear samples, in both pathological conditions, and in response to treatment. However, the sheer number of cells along the cochlea makes manual quantification impractical. Machine learning can be used to overcome this challenge by automating the quantification process but requires a vast and diverse dataset for effective training. In this study, we present a large collection of annotated cochlear hair-cell datasets, labeled with commonly used hair-cell markers and imaged using various fluorescence microscopy techniques. The collection includes samples from mouse, human, pig and guinea pig cochlear tissue, from normal conditions and following in-vivo and in-vitro ototoxic drug application. The dataset includes over 90'000 hair cells, all of which have been manually identified and annotated as one of two cell types: inner hair cells and outer hair cells. This dataset is the result of a collaborative effort from multiple laboratories and has been carefully curated to represent a variety of imaging techniques. With suggested usage parameters and a well-described annotation procedure, this collection can facilitate the development of generalizable cochlear hair cell detection models or serve as a starting point for fine-tuning models for other analysis tasks. By providing this dataset, we aim to supply other groups within the hearing research community with the opportunity to develop their own tools with which to analyze cochlear imaging data more fully, accurately, and with greater ease.

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 effects of the small molecule AC102, a pyridoindole, for its protective effects on residual hearing in CI. We show that AC102 significantly preserves hearing thresholds across the whole cochlea 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. AC102s effects are likely elicited during the inflammatory phase of electrode insertion trauma (EIT) and mediated by anti-apoptotic and anti-inflammatory properties, as uncovered by an in vitro assay of ethanol induced apoptosis and evaluation of mRNA expression of pro-inflammatory cytokines in an organotypic ex vivo model of EIT. The results in this study highlight AC102 as a promising compound for the attenuation of EIT during CI. Moreover, as the inflammatory response in cochlear implantation shares similarities to other etiologies of SNHL, a beneficial effect of AC102 can be inferred for other inner ear conditions as well.