RARE DISEASE
Neuropathy with hearing impairment
Neuropathy with hearing impairment
Neuropathy with hearing impairment
Drug discovery
0
drugs
With orphan designations
Overview
Neuropathy with hearing impairment encompasses conditions like Auditory Neuropathy Spectrum Disorder (ANSD) and peripheral neuropathy-related hearing loss, characterized by disrupted auditory signal transmission despite preserved outer hair cell function. Patients often exhibit normal to severe hearing thresholds but face significant speech perception challenges, especially in noise. Etiologies include genetic mutations (e.g., MPZ, PMP22), neonatal complications, and systemic neuropathies. Diagnosis combines abnormal auditory brainstem responses with intact otoacoustic emissions [1][6][11][14].
Population
Burden
Functional impact: Disproportionate speech discrimination deficits worsen quality of life and communication [1][6][16].
Cognitive risks: Linked to 20%–94% increased dementia incidence in adults with hearing impairment [9][14].
Economic/clinical: Requires lifelong multidisciplinary care, with 88.9% of ANSD patients showing minimal hearing aid benefit [2][12][16].
Therapies
Cochlear implants: Improve speech perception in ANSD by directly stimulating the auditory nerve [6][13][16].
Hearing aids/FM systems: Provide variable benefit, with FM systems enhancing signal-to-noise ratio [2][8][16].
Pharmacotherapy: Glucocorticoids for sudden sensorineural hearing loss; limited efficacy in chronic cases [3][16].
Categories: rare developmental anomalies during embryogenesis, rare genetic diseases, rare neurological diseases, rare otorhinolaryngological diseases
Research Papers
183 drug discovery papers about Neuropathy with hearing impairment. Recent publications:
183 drug discovery papers about Neuropathy with hearing impairment. Recent publications:
categories:
Small molecules
small molecules
2025-08-30 | Mitophagy Activation by N-Acetylcysteine Protects against Mic60 Deficiency-Induced Auditory Neuropathy.
Auditory neuropathy (AN) is a sensorineural hearing loss that impairs speech perception, but its mechanisms and treatments remain limited. Mic60, essential for the mitochondrial contact site and cristae organizing system, is linked to neurological disorders, yet its role in the auditory system remains unclear. We demonstrate that Mic60+/- mice develop progressive hearing loss from 6 months of age, with reduced auditory brainstem response amplitudes despite preserved outer hair cell function, consistent with AN. Mitochondrial abnormalities in spiral ganglion neurons (SGNs) emerge by 3 months, followed by mitochondrial loss and SGN degeneration, indicating progressive auditory neuron dysfunction. In vitro, Mic60 deficiency disrupts mitochondrial respiration, reversible by N-acetylcysteine (NAC). NAC treatment preserves mitochondrial integrity and rescues hearing by enhancing mitophagy. Our findings establish Mic60+/- mice as an AN animal model, highlight the role of Mic60 in the mitochondria of primary auditory neurons, and identify NAC as a potential AN treatment.
2024-02-16 | The human OPA1delTTAG mutation induces adult onset and progressive auditory neuropathy in mice.
Dominant optic atrophy (DOA) is one of the most prevalent forms of hereditary optic neuropathies and is mainly caused by heterozygous variants in OPA1, encoding a mitochondrial dynamin-related large GTPase. The clinical spectrum of DOA has been extended to a wide variety of syndromic presentations, called DOAplus, including deafness as the main secondary symptom associated to vision impairment. To date, the pathophysiological mechanisms underlying the deafness in DOA remain unknown. To gain insights into the process leading to hearing impairment, we have analyzed the Opa1delTTAG mouse model that recapitulates the DOAplus syndrome through complementary approaches combining morpho-physiology, biochemistry, and cellular and molecular biology. We found that Opa1delTTAG mutation leads an adult-onset progressive auditory neuropathy in mice, as attested by the auditory brainstem response threshold shift over time. However, the mutant mice harbored larger otoacoustic emissions in comparison to wild-type littermates, whereas the endocochlear potential, which is a proxy for the functional state of the stria vascularis, was comparable between both genotypes. Ultrastructural examination of the mutant mice revealed a selective loss of sensory inner hair cells, together with a progressive degeneration of the axons and myelin sheaths of the afferent terminals of the spiral ganglion neurons, supporting an auditory neuropathy spectrum disorder (ANSD). Molecular assessment of cochlea demonstrated a reduction of Opa1 mRNA level by greater than 40%, supporting haploinsufficiency as the disease mechanism. In addition, we evidenced an early increase in Sirtuin 3 level and in Beclin1 activity, and subsequently an age-related mtDNA depletion, increased oxidative stress, mitophagy as well as an impaired autophagic flux. Together, these results support a novel role for OPA1 in the maintenance of inner hair cells and auditory neural structures, addressing new challenges for the exploration and treatment of OPA1-linked ANSD in patients.
2023-12-27 | NADH improves AIF dimerization and inhibits apoptosis in iPSCs-derived neurons from patients with auditory neuropathy spectrum disorder.
Auditory neuropathy spectrum disorder (ANSD) is a hearing impairment involving disruptions to inner hair cells (IHCs), ribbon synapses, spiral ganglion neurons (SGNs), and/or the auditory nerve itself. The outcomes of cochlear implants (CI) for ANSD are variable and dependent on the location of lesion sites. Discovering a potential therapeutic agent for ANSD remains an urgent requirement. Here, 293T stable transfection cell lines and patient induced pluripotent stem cells (iPSCs)-derived auditory neurons carrying the apoptosis inducing factor (AIF) p.R422Q variant were used to pursue a therapeutic regent for ANSD. Nicotinamide adenine dinucleotide (NADH) is a main electron donor in the electron transport chain (ETC). In 293T stable transfection cells with the p.R422Q variant, NADH treatment improved AIF dimerization, rescued mitochondrial dysfunctions, and decreased cell apoptosis. The effects of NADH were further confirmed in patient iPSCs-derived neurons. The relative level of AIF dimers was increased to 150.7 % (P = 0.026) from 59.2 % in patient-neurons upon NADH treatment. Such increased AIF dimerization promoted the mitochondrial import of coiled-coil-helix-coiled-coil-helix domain-containing protein 4 (CHCHD4), which further restored mitochondrial functions. Similarly, the content of mitochondrial calcium (mCa2+) was downregulated from 136.7 % to 102.3 % (P = 0.0024) in patient-neurons upon NADH treatment. Such decreased mCa2+ levels inhibited calpain activity, ultimately reducing the percentage of apoptotic cells from 30.5 % to 21.1 % (P = 0.021). We also compared the therapeutic effects of gene correction and NADH treatment on hereditary ANSD. NADH treatment had comparable restorative effects on functions of ANSD patient-specific cells to that of gene correction. Our findings offer evidence of the molecular mechanisms of ANSD and introduce NADH as a potential therapeutic agent for ANSD therapy.
2023-08-17 | Activation of Nrf2 inhibits ferroptosis and protects against oxaliplatin-induced ototoxicity.
Oxaliplatin, as a third-generation platinum-based anticancer drug, is widely used in tumor therapy of many systems. Clinically, oxaliplatin has a number of serious side effects, most notably neuropathy and ototoxicity. The degeneration of cochlear hair cells is the main reason for the hearing loss caused by platinum-based drugs. However, the mechanism of oxaliplatin-induced cochlear hair cell death remains unclear. Ferroptosis is a novel cell injury pattern triggered by the accumulation of iron hydroperoxides in lipids and dependent on the participation of iron ions, which plays an important role in a variety of diseases. Whether ferroptosis is involved in oxaliplatin-induced ototoxicity has not been reported. In this study, we observed that oxaliplatin treatment resulted in lipid peroxidation and reactive oxygen species (ROS) accumulation in OC1 cells, which may be an early alteration in the occurrence of ferroptosis. Additional treatment with ferroptosis inducer or inhibitor significantly aggravated or ameliorated oxaliplatin-induced cytotoxicity. Similarly, inhibition of ferroptosis also protected cochlear hair cells against oxaliplatin-induced injury. In addition, the expression of nuclear factor erythroid 2-related factor2 (Nrf2) and heme oxygenase-1 (HO-1) was significantly increased after oxaliplatin treatment, and treatment with the Nrf2 agonist, resveratrol, dramatically attenuated cochlear hair cell damage induced by oxaliplatin. Activation of Nrf2 significantly decreased the expression of iron regulatory protein 2 (IRP-2) and reversed the expression of glutathione peroxidase 4 (GPX4). Collectively, our results demonstrated that activation of Nrf2 alleviates oxaliplatin-induced cochlear hair cell damage by inhibiting ferroptosis, which may be a new mechanism of oxaliplatin-induced ototoxicity.
2023-02-09 | AIFM1 variants associated with auditory neuropathy spectrum disorder cause apoptosis due to impaired apoptosis-inducing factor dimerization.
Auditory neuropathy spectrum disorder (ANSD) represents a variety of sensorineural deafness conditions characterized by abnormal inner hair cells and/or auditory nerve function, but with the preservation of outer hair cell function. ANSD represents up to 15% of individuals with hearing impairments. Through mutation screening, bioinformatic analysis and expression studies, we have previously identified several apoptosis-inducing factor (AIF) mitochondria-associated 1 (AIFM1) variants in ANSD families and in some other sporadic cases. Here, to elucidate the pathogenic mechanisms underlying each AIFM1 variant, we generated AIF-null cells using the clustered regularly interspersed short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) system and constructed AIF-wild type (WT) and AIF-mutant (mut) (p.T260A, p.R422W, and p.R451Q) stable transfection cell lines. We then analyzed AIF structure, coenzyme-binding affinity, apoptosis, and other aspects. Results revealed that these variants resulted in impaired dimerization, compromising AIF function. The reduction reaction of AIF variants had proceeded slower than that of AIF-WT. The average levels of AIF dimerization in AIF variant cells were only 34.5%‒49.7% of that of AIF-WT cells, resulting in caspase-independent apoptosis. The average percentage of apoptotic cells in the variants was 12.3%‒17.9%, which was significantly higher than that (6.9%‒7.4%) in controls. However, nicotinamide adenine dinucleotide (NADH) treatment promoted the reduction of apoptosis by rescuing AIF dimerization in AIF variant cells. Our findings show that the impairment of AIF dimerization by AIFM1 variants causes apoptosis contributing to ANSD, and introduce NADH as a potential drug for ANSD treatment. Our results help elucidate the mechanisms of ANSD and may lead to the provision of novel therapies. 听神经病谱系障碍（ANSD）属于感音神经性耳聋，其特征为内毛细胞和/或听觉神经元的功能异常，但外毛细胞的功能正常。在听力障碍患者中，听神经病谱系障碍的发病率高达15%。我们前期通过突变筛查、生物信息学分析和蛋白表达等检测，在ANSD家系和某些散发病例中发现了凋亡诱导因子1（AIFM1）基因的几种点突变。为阐明AIFM1突变体的致病机制，本文使用CRISPR/Cas9系统构建了凋亡诱导因子（AIF）蛋白敲除的细胞系，及其稳定转染野生型和突变型AIF 蛋白（p.T260A、p.R422W和p.R451Q）的细胞系，并且分析了AIF蛋白结构、AIF与辅酶的亲和力及细胞凋亡等情况。结果显示，上述AIF突变体可导致AIF蛋白二聚体形成障碍，损害AIF蛋白的生理功能。突变型AIF蛋白的还原速率显著低于野生型AIF蛋白。且在AIF突变型细胞系中，AIF蛋白的二聚体含量仅为AIF野生型细胞系的34.5%～49.7%，导致非caspase依赖性细胞凋亡。AIF突变型细胞系中凋亡细胞的平均百分比为12.3%~17.9%，显著高于对照组的6.9%~7.4%。特别是，烟酰胺腺嘌呤二核苷酸（NADH）处理显著提高AIF突变型细胞中的AIF蛋白二聚体含量，从而降低细胞凋亡。结果表明：AIFM1突变引起AIF蛋白二聚体形成障碍，使得细胞凋亡增加，导致ANSD发生；NADH是ANSD的潜在治疗药物。我们的研究结果有助于阐明ANSD的发病机制，并可能提供新的治疗方案。. 听神经病谱系障碍（ANSD）属于感音神经性耳聋，其特征为内毛细胞和/或听觉神经元的功能异常，但外毛细胞的功能正常。在听力障碍患者中，听神经病谱系障碍的发病率高达15%。我们前期通过突变筛查、生物信息学分析和蛋白表达等检测，在ANSD家系和某些散发病例中发现了凋亡诱导因子1（AIFM1）基因的几种点突变。为阐明AIFM1突变体的致病机制，本文使用CRISPR/Cas9系统构建了凋亡诱导因子（AIF）蛋白敲除的细胞系，及其稳定转染野生型和突变型AIF 蛋白（p.T260A、p.R422W和p.R451Q）的细胞系，并且分析了AIF蛋白结构、AIF与辅酶的亲和力及细胞凋亡等情况。结果显示，上述AIF突变体可导致AIF蛋白二聚体形成障碍，损害AIF蛋白的生理功能。突变型AIF蛋白的还原速率显著低于野生型AIF蛋白。且在AIF突变型细胞系中，AIF蛋白的二聚体含量仅为AIF野生型细胞系的34.5%～49.7%，导致非caspase依赖性细胞凋亡。AIF突变型细胞系中凋亡细胞的平均百分比为12.3%~17.9%，显著高于对照组的6.9%~7.4%。特别是，烟酰胺腺嘌呤二核苷酸（NADH）处理显著提高AIF突变型细胞中的AIF蛋白二聚体含量，从而降低细胞凋亡。结果表明：AIFM1突变引起AIF蛋白二聚体形成障碍，使得细胞凋亡增加，导致ANSD发生；NADH是ANSD的潜在治疗药物。我们的研究结果有助于阐明ANSD的发病机制，并可能提供新的治疗方案。
proteins
2024-09-26 | Stub1 promotes degradation of the activated Diaph3: A negative feedback regulatory mechanism of the actin nucleator.
The formin protein Diaph3 is an actin nucleator that regulates numerous cytoskeleton-dependent cellular processes through the activation of actin polymerization. Expression and activity of Diaph3 is tightly regulated: lack of Diaph3 results in developmental defects and embryonic lethality in mice, while overexpression of Diaph3 causes auditory neuropathy. It is known that Diaph3 homophilic interactions include the intramolecular interaction of its Dia-inhibitory domain (DID)-diaphanous autoregulatory domain (DAD) domains and the intermolecular interactions of DD-DD domains or FH2-FH2 domains. However, the physiological significance of these interactions in Diaph3 protein stability and activity is not fully understood. In this study, we show that FH2-FH2 interaction promotes Diaph3 activity, while DID-DAD and DD-DD interactions inhibit Diaph3 activity through distinct mechanisms. DID-DAD interaction is responsible for the autoinhibition of Diaph3 protein, which is disrupted by binding of Rho GTPases. Interestingly, we find that DID-DAD interaction stabilizes the expression of each DID or DAD domain against proteasomal-mediated degradation. Disruption of DID-DAD interaction by RhoA binding or M1041A mutation causes increased Diaph3 activity and accelerated degradation of the activated Diaph3 protein. Further, the activated Diaph3 is ubiquitinated at K1142/1143/1144 lysine residues by the E3 ligase Stub1. Expression of Stub1 is causally related to the stability and activity of Diaph3. Knockdown of Stub1 in mouse cochlea results in hair cell stereocilia defects, neuronal degeneration, and hearing loss, resembling the phenotypes of mice overexpressing Diaph3. Thus, our study reports a novel regulatory mechanism of Diaph3 protein expression and activity whereby the active but not inactive Diaph3 is readily degraded to prevent excessive actin polymerization.
2024-08-23 | Hidden hearing loss in a Charcot-Marie-Tooth type 1A mouse model.
Hidden hearing loss (HHL), a recently described auditory neuropathy characterized by normal audiometric thresholds but reduced sound-evoked cochlear compound action potentials, has been proposed to contribute to hearing difficulty in noisy environments in people with normal hearing thresholds and has become a widespread complaint. While most studies on HHL pathogenesis have focused on inner hair cell (IHC) synaptopathy, we recently showed that transient auditory nerve (AN) demyelination also causes HHL in mice. To test the effect of myelinopathy on hearing in a clinically relevant model, we studied a mouse model of Charcot-Marie-Tooth type 1A (CMT1A), the most prevalent hereditary peripheral neuropathy in humans. CMT1A mice exhibited the functional hallmarks of HHL together with disorganization of AN heminodes near the IHCs with minor loss of AN fibers. These results support the hypothesis that mild disruptions of AN myelination can cause HHL and that heminodal defects contribute to the alterations in the sound-evoked cochlear compound action potentials seen in this mouse model. Furthermore, these findings suggest that patients with CMT1A or other mild peripheral neuropathies are likely to suffer from HHL. Furthermore, these results suggest that studies of hearing in patients with CMT1A might help develop robust clinical tests for HHL, which are currently lacking.
2021-08-17 | Functional P2X7 Receptors in the Auditory Nerve of Hearing Rodents Localize Exclusively to Peripheral Glia.
P2X7 receptors (P2X7Rs) are associated with numerous pathophysiological mechanisms, and this promotes them as therapeutic targets for certain neurodegenerative conditions. However, the identity of P2X7R-expressing cells in the nervous system remains contentious. Here, we examined P2X7R functionality in auditory nerve cells from rodents of either sex, and determined their functional and anatomic expression pattern. In whole-cell recordings from rat spiral ganglion cultures, the purinergic agonist 2',3'-O-(4-benzoylbenzoyl)-ATP (BzATP) activated desensitizing currents in spiral ganglion neurons (SGNs) but non-desensitizing currents in glia that were blocked by P2X7R-specific antagonists. In imaging experiments, BzATP gated sustained Ca2+ entry into glial cells. BzATP-gated uptake of the fluorescent dye YO-PRO-1 was reduced and slowed by P2X7R-specific antagonists. In rats, P2X7Rs were immuno-localized predominantly within satellite glial cells (SGCs) and Schwann cells (SCs). P2X7R expression was not detected in the portion of the auditory nerve within the central nervous system. Mouse models allowed further exploration of the distribution of cochlear P2X7Rs. In GENSAT reporter mice, EGFP expression driven via the P2rx7 promoter was evident in SGCs and SCs but was undetectable in SGNs. A second transgenic model showed a comparable cellular distribution of EGFP-tagged P2X7Rs. In wild-type mice the discrete glial expression was confirmed using a P2X7-specific nanobody construct. Our study shows that P2X7Rs are expressed by peripheral glial cells, rather than by afferent neurons. Description of functional signatures and cellular distributions of these enigmatic proteins in the peripheral nervous system (PNS) will help our understanding of ATP-dependent effects contributing to hearing loss and other sensory neuropathies.SIGNIFICANCE STATEMENT P2X7 receptors (P2X7Rs) have been the subject of much scrutiny in recent years. They have been promoted as therapeutic targets in a number of diseases of the nervous system, yet the specific cellular location of these receptors remains the subject of intense debate. In the auditory nerve, connecting the inner ear to the brainstem, we show these multimodal ATP-gated channels localize exclusively to peripheral glial cells rather than the sensory neurons, and are not evident in central glia. Physiologic responses in the peripheral glia display classical hallmarks of P2X7R activation, including the formation of ion-permeable and also macromolecule-permeable pores. These qualities suggest these proteins could contribute to glial-mediated inflammatory processes in the auditory periphery under pathologic disease states.
2016-07-27 | Neural stem/progenitor cell properties of glial cells in the adult mouse auditory nerve.
The auditory nerve is the primary conveyor of hearing information from sensory hair cells to the brain. It has been believed that loss of the auditory nerve is irreversible in the adult mammalian ear, resulting in sensorineural hearing loss. We examined the regenerative potential of the auditory nerve in a mouse model of auditory neuropathy. Following neuronal degeneration, quiescent glial cells converted to an activated state showing a decrease in nuclear chromatin condensation, altered histone deacetylase expression and up-regulation of numerous genes associated with neurogenesis or development. Neurosphere formation assays showed that adult auditory nerves contain neural stem/progenitor cells (NSPs) that were within a Sox2-positive glial population. Production of neurospheres from auditory nerve cells was stimulated by acute neuronal injury and hypoxic conditioning. These results demonstrate that a subset of glial cells in the adult auditory nerve exhibit several characteristics of NSPs and are therefore potential targets for promoting auditory nerve regeneration.
2007-04-05 | Tissue-specific effects of wild-type and mutant connexin 31: a role in neurite outgrowth.
Channels formed by connexins (Cx), the major protein subunits of gap junctions, allow passage of ions and molecular messengers between cells to provide a mechanism of synchronized cellular response. Twenty human Cx isoforms have been identified and mutations in the gene GJB3 encoding the 31 kDa isoform, Cx31, can cause dominant or recessive skin disease, dominant or recessive deafness or dominant neuropathy with deafness. Cx31 is expressed in differentiating keratinocytes in skin. Here, we also demonstrate endogenous Cx31 expression in human neuronal cell lines, particularly in differentiated neurones. Exogenous Cx31 expression induced neurite outgrowth in human neuronal cell lines, but not differentiation in primary human keratinocytes. Though neither the neuropathy and hearing loss mutation (66delD)Cx31 nor the skin disease associated mutation (R42P)Cx31 is able to traffic to the plasma membrane, the R42P mutant induced neurite outgrowth to a level equal to wild-type Cx31. In contrast, there was significantly reduced neurite outgrowth after (66delD)Cx31 expression. In addition to indicating a potential disease mechanism for the neuropathy/deafness mutation, this work demonstrates a tissue-specific function for Cx31.
cell therapies
2026-05-15 | Mesenchymal vs. induced pluripotent stem cells: potential for spiral ganglion neuron regeneration in auditory neuropathy.
Auditory neuropathy is a distinct form of sensorineural hearing loss characterized by dysfunction or degeneration of primary auditory neurons, also known as spiral ganglion neurons (SGNs), which transmit acoustic information from the cochlea to the brain. Increasing evidence indicates that SGNs are particularly susceptible to degeneration induced by noise exposure, ototoxic agents, genetic mutations, or aging, often preceding the loss of cochlear mechanosensory hair cells, and thus represents a critical target for regenerative intervention for auditory neuropathy. Stem cell-based approaches have emerged as promising strategies to restore auditory nerve function. In particular, the generation of otic neuronal progenitors (ONPs) capable of replacing damaged SGNs offers a translationally relevant avenue for therapy. Among candidate sources, mesenchymal stem cells (MSCs) and induced pluripotent stem cells (iPSCs) offer distinct biological and translational advantages. iPSCs provide robust pluripotency and developmental recapitulation capacity, enabling efficient differentiation toward otic neuronal lineages, whereas MSCs offer immunomodulatory properties and paracrine neurotrophic support with lower tumorigenic risk. This mini-review critically compares MSC and iPSC-derived ONPs in terms of differentiation efficiency, neuronal maturation, integration potential, immunogenicity, and scalability. We further discuss emerging complementary strategies, including ONP transplantation, glial cell reprogramming and extracellular vesicle-based therapies. Together, these approaches highlight converging regenerative paradigms aimed at restoring auditory neuron function in neuropathic hearing loss.
2026-01-20 | Evaluating Cochlear Implantation Outcomes in Charcot-Marie-Tooth Disease: A Case Series Analysis of Genetic Profiles and Intervention Timing.
Charcot-Marie-Tooth disease (CMT) is a hereditary neuropathy that may present with sensorineural hearing loss (SNHL) or auditory neuropathy spectrum disorder (ANSD). Cochlear implants (CIs) have been used to rehabilitate hearing loss in CMT, but their effectiveness remains poorly understood due to the central and peripheral neurological complexities of the disease. Clinical capsule report. Two adult CMT patients and 2 pediatric CMT patients. Cochlear implantation. Preoperative clinical profiles and postoperative auditory performance. Case 1: A 60-year-old woman with bilateral ANSD and comorbid multiple sclerosis (MS) achieved significant speech perception improvement (CNC: 8%-68%, AzBio: 64%) 1 year post-CI. Case 2: A 20-month-old boy with GJB1 -associated CMT1X and developmental delays exhibited rapid auditory gains (MLNT: 100%) following CI. Case 3: A 12-year-old boy with AIFM1 -related ANSD and mitochondrial dysfunction achieved moderate speech recognition (CNC: 56%, AzBio: 75%) but remained limited in noisy environments. Case 4: A 32-year-old man with PRPS1 -associated CMTX5 and profound prelingual SNHL showed improved sound awareness (20-30 dB HL) post-CI but had no speech perception gains due to prolonged auditory deprivation. Cochlear implantation in CMT patients demonstrates variable but meaningfully beneficial auditory outcomes, with early intervention yielding the most favorable results. A personalized approach incorporating genetic profiling, tailored rehabilitation strategies, and setting realistic patient expectations is essential to optimizing outcomes.
2025-12-19 | MSC-sEV Promote Regeneration of Cochlear Spiral Ganglion Neurons and Myelin Sheaths in 3D Culture System.
Spiral ganglion neurons (SGNs) play a crucial role in auditory signal transmission, and their degeneration is a significant factor in hearing loss. The protection of SGNs remains a central focus in auditory neuropathy treatment, while repairing their surrounding myelin sheaths has often been underestimated. To better simulate the cochlear neural microenvironment and enhance regenerative therapy, we developed a regenerative strategy using mesenchymal stem cell-derived small extracellular vesicles (MSC-sEV) combined with a biomimetic 3D cochlear culture system. Our results demonstrate that MSC-sEV significantly promotes Schwann cell migration and proliferation, thereby supporting the structural integrity and trophic environment essential for SGN function. Simultaneously, MSC-sEV treatment markedly enhances SGN survival, axonal outgrowth, and neural network reconstruction within the 3D culture model, mimicking the in vivo cochlear microenvironment. Importantly, in an ouabain-induced auditory neuropathy model, MSC-sEV administration attenuated neuronal loss, preserved SGN-hair cell connectivity, and facilitated functional recovery. By targeting both SGNs and their myelin sheaths, this dual-action strategy effectively reconstructs the neuroglial functional unit, fostering a regenerative microenvironment for auditory circuit repair.
2025-12-08 | Neural stem cell-loaded biohybrid hydrogel improves cochlear implants by electrode-neural coupling and neural regeneration.
Background: Contemporary cochlear implants (CIs) face unresolved dual challenges: biomechanical-electrochemical mismatch at the electrode-tissue interface and progressive spiral ganglion neuron (SGN) degeneration, severely limiting long-term auditory restoration. Integrating regenerative medicine with bioelectronic engineering offers promise to overcome these bottlenecks. Methods: A biohybrid neural interface was developed by embedding neural stem cells (NSCs) in photopolymerized poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS)/collagen hydrogel. Physicochemical properties were characterized via rheometry, electron microscopy, and electrochemical impedance spectroscopy. In vitro NSC responses (proliferation/differentiation) were quantified with EdU/Tuj1 assays. Therapeutic efficacy was evaluated in guinea pigs with ouabain-induced auditory neuropathy using auditory brainstem response (ABR) thresholds and immunohistochemical SGN quantification, comparing CI-alone versus NSC-hydrogel-CI groups. Results: The photopolymerized PEDOT:PSS/collagen hydrogel demonstrated cochlear tissue-matched viscoelastic properties (storage modulus: 8.7-12.4 kPa) with injectable sol-gel transition capability, while exhibiting enhanced bioelectronic coupling through high electrical conductivity (1.3 ± 0.1 S/m) and 97.7% reduction in charge transfer resistance. This electroactive microenvironment significantly promoted NSC proliferation (+51.6%) and neuronal differentiation (+76.4%) in vitro, effects further amplified by CI stimulation to achieve +71.5% proliferation and +23.4% neuronal differentiation. In vivo evaluation using ouabain-induced auditory neuropathy guinea pigs revealed substantial functional recovery, with ABR threshold improvements of 18.8-28.8 dB across 4-12 kHz frequencies by post-operative day 14, correlating with significant SGN regeneration in the apical turn (+11.14 cells/0.01 mm²), whereas CI-alone controls exhibited negligible recovery. Conclusions: This NSC-laden conductive hydrogel establishes a self-reinforcing therapeutic paradigm that simultaneously resolves electrode-tissue mismatch through optimized bioelectronic interfacing and reverses neurodegeneration via stem cell-mediated SGN regeneration. The dual-function platform pioneers active neural repair for next-generation neuroprosthetics.
2025-06-04 | A novel BCAP31 variant associated with nonsyndromic auditory neuropathy spectrum disorder: mitochondrial dysfunction, cisplatin sensitivity, and amenability to mitochondrial transplantation.
A novel in-frame insertion variant in the B-Cell Receptor-Associated Protein 31 (BCAP31) gene, which encodes a crucial ER membrane protein involved in the quality control and transport of transmembrane proteins, as well as in ER-mitochondria apoptotic signaling, was determined in a family demonstrating X-linked, recessive, nonsyndromic auditory neuropathy spectrum disorder (ANSD). Exome sequencing analysiswas followed by bioinformatics analysis to identify the cause of hearing loss in a family whose pedigree indicated an X-linked recessive mode of inheritance. Immunohistochemistry was performed to locate Bcap31 in the mouse cochlea. Mitochondrial function was evaluated by measuring intracellular ATP, ROS and mitochondrial membrane potential in control and patient-derived lymphoblastoid cells (LCLs) before and after the administration of mitochondria isolated from human umbilical cord mesenchymal stem cells (UC-MSCs). ANSD observed in our study is characterized by initial inner hair cell damage, followed by accelerated degeneration of cochlear outer hair cells. Functional studies of patient-derived LCLs revealed mitochondrial dysfunction, evidenced by increased ROS, reduced ATP levels, and decreased mitochondrial membrane potential compared with normal LCLs. Further, these cells demonstrated heightened sensitivity to cisplatin-induced apoptosis, as indicated by the increased proapoptotic gene expression. Notably, the administration of mitochondria isolated from umbilical cord mesenchymal stem cells significantly restored mitochondrial dysfunction and alleviated cisplatin-induced cytotoxicity in the patient-derived cells. These results indicate BCAP31 dysfunction as a potential cause of transient ANSD, progressing to sensorineural hearing loss through mitochondrial impairment. Furthermore, they highlighted the therapeutic potential of allogenic mitochondrial transplantation as a novel strategy for treating hearing loss with an underlying component of mitochondrial dysfunction. This study contributes to the understanding of BCAP31's role in auditory neuropathy and mitochondrial health.
gene therapies
2026-04-24 | Auditory neuropathy as the first sign of leptomeningeal metastasis.
Auditory neuropathy is a hearing disorder characterized by impaired temporal coding of acoustic signals in the auditory nerve fibers, resulting in abnormal auditory perceptions relying on temporal cues. We describe the case of a woman with a history of cancer who developed auditory neuropathy as the first manifestation of leptomeningeal metastasis. A woman in her sixties complained of severe difficulties in understanding speech despite preserved sensitivity to sounds, which had begun two months before audiological assessment. Her past medical history was remarkable for an occult cancer, possibly breast cancer, diagnosed seven years earlier. Pure-tone audiometry showed mild bilateral sensorineural hearing loss associated with markedly reduced speech intelligibility. Otoacoustic emissions were normal, indicating preserved outer hair cell function, whereas auditory brainstem responses (ABRs) were absent despite preserved hearing thresholds. Contrast-enhanced brain magnetic resonance imaging (MRI) only demonstrated bilateral enhancement of the eighth cranial nerve. However, a brain MRI performed one month later revealed diffuse leptomeningeal enhancement, while cerebrospinal fluid (CSF) cytology was positive for atypical malignant cells, both findings consistent with leptomeningeal metastasis. This case illustrates that the onset of auditory neuropathy in a patient with a clinical history of cancer may represent an early clinical sign of leptomeningeal metastasis, highlighting the importance of prompt neuroimaging and CSF analysis.
2026-03-01 | Precise and efficient DNA base editing restores normal hearing in adult DFNB9 mouse model.
Mutations in the OTOF gene, which cause autosomal recessive non-syndromic hearing loss, DFNB9, are a leading cause of auditory neuropathy. Gene augmentation and RNA and DNA editing have been used to restore the auditory function of mouse models, and gene augmentation has even been used in patients with DFNB9. However, the therapeutic time window for DFNB9 treatment is largely unknown. We screened multiple adenine base editors to identify an optimal editor for correcting the pathogenic Otof c.2815C>T (p.Gln939∗) mutation. The selected editor was delivered to the cochlea of Otof-deficient mice at different postnatal ages using an adeno-associated-virus-mediated strategy. Auditory function was assessed in the treated Otof-deficient mice, while safety was evaluated in wild-type mice. Nme2ABE8e exhibited superior on-target editing efficiency compared with other base editors. Adeno-associated-virus-mediated delivery of Nme2ABE8e to 1-month-old adult Otof-deficient mice restored auditory function to near-normal levels, with sustained effects for at least 6 months. Importantly, treatment at 2, 3, and 4 months of age also resulted in hearing improvement, indicating an extended therapeutic time window. Comprehensive safety assessments revealed no detectable ototoxicity or neurological deficits. These results underscore the safety and efficacy of Nme2ABE8e for DFNB9 and suggest that patients with DFNB9 may have a relatively long therapeutic time window for gene therapy. This work was funded by the National Key R&D Program of China, the National Natural Science Foundation of China, and other governmental and institutional funding sources.
2026-02-28 | Auditory Neuropathy: Challenges and Significant Progress in Diagnosis and Treatment
ABSTRACT Auditory neuropathy (AN) is a complex disorder where sensorineural hearing impairment occurs due to abnormal neural encoding to sound stimuli. This can be caused by damage to sensory inner hair cells (IHCs)‐presynapse, IHC ribbon synapses, or spiral ganglion neurons via post‐synapse. Genetic factors play a significant role in AN. Audiological assessment such as otoacoustic emissions, auditory brainstem responses, and speech audiometry is crucial in diagnosing auditory neuropathy. Hearing aids and cochlear implants are currently commonly used methods for interventing AN. Owing to the intricate nature of the disease's pathogenesis, a standardized diagnostic approach has yet to be established, and therapeutic options remain significantly constrained. However, it is noteworthy that breakthrough progress has been made in the treatment of AN. In 2024, Chinese researchers used adeno‐associated virus gene therapy for AN patients with OTOF gene mutations, and achieved exceptionally good results in clinical trials. This review focuses on auditory neuropathy, covering its theoretical foundations, epidemiology, diagnostic techniques, treatment strategies, clinical practice, as well as future directions and controversie.
2026-01-21 | A novel minimally invasive stereotaxic technique to target inner ear neurons in the mouse.
Sensorineural hearing loss (SNHL), a leading cause of disability worldwide, arises from damage to hair cells (HCs) or spiral ganglion neurons (SGNs) within the cochlea. Among its etiologies, auditory neuropathy (AN) is characterized by disrupted signal transmission due to SGN damage. Traditional interventions, such as hearing aids and cochlear implants, provide limited benefit in cases of AN, where neuronal damage impairs signal transduction to the brain. Emerging regenerative therapies, including cell replacement and gene delivery, hold potential to restore SGN function, but their application is limited by challenges in delivering therapeutic agents to cochlear targets. In this study, we developed a novel stereotaxic approach for minimally invasive, precise delivery of therapeutic agents to murine SGNs. Utilizing pre-determined coordinates, we successfully accessed the cochlea and SGNs. Immunohistochemistry confirmed accurate delivery and integration of therapeutic agents. Functional hearing assessments showed that the approach preserved HC function and demonstrated minimal adverse effects. This technique offers a scalable platform for advancing cell and gene therapies aimed at restoring auditory function in AN and other forms of SNHL.
2025-11-14 | Characteristic cortical alterations in auditory neuropathy: An EEG study.
Auditory neuropathy (AN) is a complex auditory disorder characterized by disproportionately poor speech discrimination despite preserved auditory sensitivity, substantially impacting daily communication and overall quality of life. This study conducted comprehensive audiological measurements and high-density electroencephalography (EEG) measurements in resting and auditory task states on 21 AN, 21 age-, gender-, and hearing threshold-matched sensorineural hearing loss (SNHL), and 21 age- and gender-matched normal hearing (NH) subjects. The topological network attributes, microstates, event-related potentials (ERP), cortical lateralization, phase-locking value (PLV) functional connectivity strength of EEG, and correlations with audiological indicators were compared among three groups. The results showed that in the resting state, the global field power (GFP) of microstate A differed significantly after FDR correction, with SNHL showing higher GFP 3.23 (2.46-3.93) μV than AN 2.37 (2.08-3.08) μV and NH 2.38 (2.08-2.63) μV. The transition probability (TP) from microstate A to B and from B to C were higher in SNHL than NH (both P after correction = 0.011). During task processing, N1 amplitude was lower in SNHL than NH (P after correction = 0.023), while N1 latency was shorter in AN than SNHL (P after correction = 0.006) and was correlated with low-frequency PTA (correlation coefficient = 0.362, P after correction = 0.020). AN additionally exhibited left-hemispheric lateralization (P after correction < 0.05). Source localization revealed greater cortical activation in SNHL than in AN and NH, predominantly in the superior frontal gyrus (SNHL > NH: P = 0.00020, t0.05 = 3.692, and SNHL > AN: P = 0.01140, t0.05 = -3.794). Collectively, these findings demonstrate that AN exhibits unique neural compensation patterns distinct from SNHL, supporting cortical reorganization mechanisms specific to neural dyssynchrony rather than simple auditory input reduction.
small molecules
2025-08-30 | Mitophagy Activation by N-Acetylcysteine Protects against Mic60 Deficiency-Induced Auditory Neuropathy.
Auditory neuropathy (AN) is a sensorineural hearing loss that impairs speech perception, but its mechanisms and treatments remain limited. Mic60, essential for the mitochondrial contact site and cristae organizing system, is linked to neurological disorders, yet its role in the auditory system remains unclear. We demonstrate that Mic60+/- mice develop progressive hearing loss from 6 months of age, with reduced auditory brainstem response amplitudes despite preserved outer hair cell function, consistent with AN. Mitochondrial abnormalities in spiral ganglion neurons (SGNs) emerge by 3 months, followed by mitochondrial loss and SGN degeneration, indicating progressive auditory neuron dysfunction. In vitro, Mic60 deficiency disrupts mitochondrial respiration, reversible by N-acetylcysteine (NAC). NAC treatment preserves mitochondrial integrity and rescues hearing by enhancing mitophagy. Our findings establish Mic60+/- mice as an AN animal model, highlight the role of Mic60 in the mitochondria of primary auditory neurons, and identify NAC as a potential AN treatment.
2024-02-16 | The human OPA1delTTAG mutation induces adult onset and progressive auditory neuropathy in mice.
Dominant optic atrophy (DOA) is one of the most prevalent forms of hereditary optic neuropathies and is mainly caused by heterozygous variants in OPA1, encoding a mitochondrial dynamin-related large GTPase. The clinical spectrum of DOA has been extended to a wide variety of syndromic presentations, called DOAplus, including deafness as the main secondary symptom associated to vision impairment. To date, the pathophysiological mechanisms underlying the deafness in DOA remain unknown. To gain insights into the process leading to hearing impairment, we have analyzed the Opa1delTTAG mouse model that recapitulates the DOAplus syndrome through complementary approaches combining morpho-physiology, biochemistry, and cellular and molecular biology. We found that Opa1delTTAG mutation leads an adult-onset progressive auditory neuropathy in mice, as attested by the auditory brainstem response threshold shift over time. However, the mutant mice harbored larger otoacoustic emissions in comparison to wild-type littermates, whereas the endocochlear potential, which is a proxy for the functional state of the stria vascularis, was comparable between both genotypes. Ultrastructural examination of the mutant mice revealed a selective loss of sensory inner hair cells, together with a progressive degeneration of the axons and myelin sheaths of the afferent terminals of the spiral ganglion neurons, supporting an auditory neuropathy spectrum disorder (ANSD). Molecular assessment of cochlea demonstrated a reduction of Opa1 mRNA level by greater than 40%, supporting haploinsufficiency as the disease mechanism. In addition, we evidenced an early increase in Sirtuin 3 level and in Beclin1 activity, and subsequently an age-related mtDNA depletion, increased oxidative stress, mitophagy as well as an impaired autophagic flux. Together, these results support a novel role for OPA1 in the maintenance of inner hair cells and auditory neural structures, addressing new challenges for the exploration and treatment of OPA1-linked ANSD in patients.
2023-12-27 | NADH improves AIF dimerization and inhibits apoptosis in iPSCs-derived neurons from patients with auditory neuropathy spectrum disorder.
Auditory neuropathy spectrum disorder (ANSD) is a hearing impairment involving disruptions to inner hair cells (IHCs), ribbon synapses, spiral ganglion neurons (SGNs), and/or the auditory nerve itself. The outcomes of cochlear implants (CI) for ANSD are variable and dependent on the location of lesion sites. Discovering a potential therapeutic agent for ANSD remains an urgent requirement. Here, 293T stable transfection cell lines and patient induced pluripotent stem cells (iPSCs)-derived auditory neurons carrying the apoptosis inducing factor (AIF) p.R422Q variant were used to pursue a therapeutic regent for ANSD. Nicotinamide adenine dinucleotide (NADH) is a main electron donor in the electron transport chain (ETC). In 293T stable transfection cells with the p.R422Q variant, NADH treatment improved AIF dimerization, rescued mitochondrial dysfunctions, and decreased cell apoptosis. The effects of NADH were further confirmed in patient iPSCs-derived neurons. The relative level of AIF dimers was increased to 150.7 % (P = 0.026) from 59.2 % in patient-neurons upon NADH treatment. Such increased AIF dimerization promoted the mitochondrial import of coiled-coil-helix-coiled-coil-helix domain-containing protein 4 (CHCHD4), which further restored mitochondrial functions. Similarly, the content of mitochondrial calcium (mCa2+) was downregulated from 136.7 % to 102.3 % (P = 0.0024) in patient-neurons upon NADH treatment. Such decreased mCa2+ levels inhibited calpain activity, ultimately reducing the percentage of apoptotic cells from 30.5 % to 21.1 % (P = 0.021). We also compared the therapeutic effects of gene correction and NADH treatment on hereditary ANSD. NADH treatment had comparable restorative effects on functions of ANSD patient-specific cells to that of gene correction. Our findings offer evidence of the molecular mechanisms of ANSD and introduce NADH as a potential therapeutic agent for ANSD therapy.
2023-08-17 | Activation of Nrf2 inhibits ferroptosis and protects against oxaliplatin-induced ototoxicity.
Oxaliplatin, as a third-generation platinum-based anticancer drug, is widely used in tumor therapy of many systems. Clinically, oxaliplatin has a number of serious side effects, most notably neuropathy and ototoxicity. The degeneration of cochlear hair cells is the main reason for the hearing loss caused by platinum-based drugs. However, the mechanism of oxaliplatin-induced cochlear hair cell death remains unclear. Ferroptosis is a novel cell injury pattern triggered by the accumulation of iron hydroperoxides in lipids and dependent on the participation of iron ions, which plays an important role in a variety of diseases. Whether ferroptosis is involved in oxaliplatin-induced ototoxicity has not been reported. In this study, we observed that oxaliplatin treatment resulted in lipid peroxidation and reactive oxygen species (ROS) accumulation in OC1 cells, which may be an early alteration in the occurrence of ferroptosis. Additional treatment with ferroptosis inducer or inhibitor significantly aggravated or ameliorated oxaliplatin-induced cytotoxicity. Similarly, inhibition of ferroptosis also protected cochlear hair cells against oxaliplatin-induced injury. In addition, the expression of nuclear factor erythroid 2-related factor2 (Nrf2) and heme oxygenase-1 (HO-1) was significantly increased after oxaliplatin treatment, and treatment with the Nrf2 agonist, resveratrol, dramatically attenuated cochlear hair cell damage induced by oxaliplatin. Activation of Nrf2 significantly decreased the expression of iron regulatory protein 2 (IRP-2) and reversed the expression of glutathione peroxidase 4 (GPX4). Collectively, our results demonstrated that activation of Nrf2 alleviates oxaliplatin-induced cochlear hair cell damage by inhibiting ferroptosis, which may be a new mechanism of oxaliplatin-induced ototoxicity.
2023-02-09 | AIFM1 variants associated with auditory neuropathy spectrum disorder cause apoptosis due to impaired apoptosis-inducing factor dimerization.
Auditory neuropathy spectrum disorder (ANSD) represents a variety of sensorineural deafness conditions characterized by abnormal inner hair cells and/or auditory nerve function, but with the preservation of outer hair cell function. ANSD represents up to 15% of individuals with hearing impairments. Through mutation screening, bioinformatic analysis and expression studies, we have previously identified several apoptosis-inducing factor (AIF) mitochondria-associated 1 (AIFM1) variants in ANSD families and in some other sporadic cases. Here, to elucidate the pathogenic mechanisms underlying each AIFM1 variant, we generated AIF-null cells using the clustered regularly interspersed short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) system and constructed AIF-wild type (WT) and AIF-mutant (mut) (p.T260A, p.R422W, and p.R451Q) stable transfection cell lines. We then analyzed AIF structure, coenzyme-binding affinity, apoptosis, and other aspects. Results revealed that these variants resulted in impaired dimerization, compromising AIF function. The reduction reaction of AIF variants had proceeded slower than that of AIF-WT. The average levels of AIF dimerization in AIF variant cells were only 34.5%‒49.7% of that of AIF-WT cells, resulting in caspase-independent apoptosis. The average percentage of apoptotic cells in the variants was 12.3%‒17.9%, which was significantly higher than that (6.9%‒7.4%) in controls. However, nicotinamide adenine dinucleotide (NADH) treatment promoted the reduction of apoptosis by rescuing AIF dimerization in AIF variant cells. Our findings show that the impairment of AIF dimerization by AIFM1 variants causes apoptosis contributing to ANSD, and introduce NADH as a potential drug for ANSD treatment. Our results help elucidate the mechanisms of ANSD and may lead to the provision of novel therapies. 听神经病谱系障碍（ANSD）属于感音神经性耳聋，其特征为内毛细胞和/或听觉神经元的功能异常，但外毛细胞的功能正常。在听力障碍患者中，听神经病谱系障碍的发病率高达15%。我们前期通过突变筛查、生物信息学分析和蛋白表达等检测，在ANSD家系和某些散发病例中发现了凋亡诱导因子1（AIFM1）基因的几种点突变。为阐明AIFM1突变体的致病机制，本文使用CRISPR/Cas9系统构建了凋亡诱导因子（AIF）蛋白敲除的细胞系，及其稳定转染野生型和突变型AIF 蛋白（p.T260A、p.R422W和p.R451Q）的细胞系，并且分析了AIF蛋白结构、AIF与辅酶的亲和力及细胞凋亡等情况。结果显示，上述AIF突变体可导致AIF蛋白二聚体形成障碍，损害AIF蛋白的生理功能。突变型AIF蛋白的还原速率显著低于野生型AIF蛋白。且在AIF突变型细胞系中，AIF蛋白的二聚体含量仅为AIF野生型细胞系的34.5%～49.7%，导致非caspase依赖性细胞凋亡。AIF突变型细胞系中凋亡细胞的平均百分比为12.3%~17.9%，显著高于对照组的6.9%~7.4%。特别是，烟酰胺腺嘌呤二核苷酸（NADH）处理显著提高AIF突变型细胞中的AIF蛋白二聚体含量，从而降低细胞凋亡。结果表明：AIFM1突变引起AIF蛋白二聚体形成障碍，使得细胞凋亡增加，导致ANSD发生；NADH是ANSD的潜在治疗药物。我们的研究结果有助于阐明ANSD的发病机制，并可能提供新的治疗方案。. 听神经病谱系障碍（ANSD）属于感音神经性耳聋，其特征为内毛细胞和/或听觉神经元的功能异常，但外毛细胞的功能正常。在听力障碍患者中，听神经病谱系障碍的发病率高达15%。我们前期通过突变筛查、生物信息学分析和蛋白表达等检测，在ANSD家系和某些散发病例中发现了凋亡诱导因子1（AIFM1）基因的几种点突变。为阐明AIFM1突变体的致病机制，本文使用CRISPR/Cas9系统构建了凋亡诱导因子（AIF）蛋白敲除的细胞系，及其稳定转染野生型和突变型AIF 蛋白（p.T260A、p.R422W和p.R451Q）的细胞系，并且分析了AIF蛋白结构、AIF与辅酶的亲和力及细胞凋亡等情况。结果显示，上述AIF突变体可导致AIF蛋白二聚体形成障碍，损害AIF蛋白的生理功能。突变型AIF蛋白的还原速率显著低于野生型AIF蛋白。且在AIF突变型细胞系中，AIF蛋白的二聚体含量仅为AIF野生型细胞系的34.5%～49.7%，导致非caspase依赖性细胞凋亡。AIF突变型细胞系中凋亡细胞的平均百分比为12.3%~17.9%，显著高于对照组的6.9%~7.4%。特别是，烟酰胺腺嘌呤二核苷酸（NADH）处理显著提高AIF突变型细胞中的AIF蛋白二聚体含量，从而降低细胞凋亡。结果表明：AIFM1突变引起AIF蛋白二聚体形成障碍，使得细胞凋亡增加，导致ANSD发生；NADH是ANSD的潜在治疗药物。我们的研究结果有助于阐明ANSD的发病机制，并可能提供新的治疗方案。
proteins
2024-09-26 | Stub1 promotes degradation of the activated Diaph3: A negative feedback regulatory mechanism of the actin nucleator.
The formin protein Diaph3 is an actin nucleator that regulates numerous cytoskeleton-dependent cellular processes through the activation of actin polymerization. Expression and activity of Diaph3 is tightly regulated: lack of Diaph3 results in developmental defects and embryonic lethality in mice, while overexpression of Diaph3 causes auditory neuropathy. It is known that Diaph3 homophilic interactions include the intramolecular interaction of its Dia-inhibitory domain (DID)-diaphanous autoregulatory domain (DAD) domains and the intermolecular interactions of DD-DD domains or FH2-FH2 domains. However, the physiological significance of these interactions in Diaph3 protein stability and activity is not fully understood. In this study, we show that FH2-FH2 interaction promotes Diaph3 activity, while DID-DAD and DD-DD interactions inhibit Diaph3 activity through distinct mechanisms. DID-DAD interaction is responsible for the autoinhibition of Diaph3 protein, which is disrupted by binding of Rho GTPases. Interestingly, we find that DID-DAD interaction stabilizes the expression of each DID or DAD domain against proteasomal-mediated degradation. Disruption of DID-DAD interaction by RhoA binding or M1041A mutation causes increased Diaph3 activity and accelerated degradation of the activated Diaph3 protein. Further, the activated Diaph3 is ubiquitinated at K1142/1143/1144 lysine residues by the E3 ligase Stub1. Expression of Stub1 is causally related to the stability and activity of Diaph3. Knockdown of Stub1 in mouse cochlea results in hair cell stereocilia defects, neuronal degeneration, and hearing loss, resembling the phenotypes of mice overexpressing Diaph3. Thus, our study reports a novel regulatory mechanism of Diaph3 protein expression and activity whereby the active but not inactive Diaph3 is readily degraded to prevent excessive actin polymerization.
2024-08-23 | Hidden hearing loss in a Charcot-Marie-Tooth type 1A mouse model.
Hidden hearing loss (HHL), a recently described auditory neuropathy characterized by normal audiometric thresholds but reduced sound-evoked cochlear compound action potentials, has been proposed to contribute to hearing difficulty in noisy environments in people with normal hearing thresholds and has become a widespread complaint. While most studies on HHL pathogenesis have focused on inner hair cell (IHC) synaptopathy, we recently showed that transient auditory nerve (AN) demyelination also causes HHL in mice. To test the effect of myelinopathy on hearing in a clinically relevant model, we studied a mouse model of Charcot-Marie-Tooth type 1A (CMT1A), the most prevalent hereditary peripheral neuropathy in humans. CMT1A mice exhibited the functional hallmarks of HHL together with disorganization of AN heminodes near the IHCs with minor loss of AN fibers. These results support the hypothesis that mild disruptions of AN myelination can cause HHL and that heminodal defects contribute to the alterations in the sound-evoked cochlear compound action potentials seen in this mouse model. Furthermore, these findings suggest that patients with CMT1A or other mild peripheral neuropathies are likely to suffer from HHL. Furthermore, these results suggest that studies of hearing in patients with CMT1A might help develop robust clinical tests for HHL, which are currently lacking.
2021-08-17 | Functional P2X7 Receptors in the Auditory Nerve of Hearing Rodents Localize Exclusively to Peripheral Glia.
P2X7 receptors (P2X7Rs) are associated with numerous pathophysiological mechanisms, and this promotes them as therapeutic targets for certain neurodegenerative conditions. However, the identity of P2X7R-expressing cells in the nervous system remains contentious. Here, we examined P2X7R functionality in auditory nerve cells from rodents of either sex, and determined their functional and anatomic expression pattern. In whole-cell recordings from rat spiral ganglion cultures, the purinergic agonist 2',3'-O-(4-benzoylbenzoyl)-ATP (BzATP) activated desensitizing currents in spiral ganglion neurons (SGNs) but non-desensitizing currents in glia that were blocked by P2X7R-specific antagonists. In imaging experiments, BzATP gated sustained Ca2+ entry into glial cells. BzATP-gated uptake of the fluorescent dye YO-PRO-1 was reduced and slowed by P2X7R-specific antagonists. In rats, P2X7Rs were immuno-localized predominantly within satellite glial cells (SGCs) and Schwann cells (SCs). P2X7R expression was not detected in the portion of the auditory nerve within the central nervous system. Mouse models allowed further exploration of the distribution of cochlear P2X7Rs. In GENSAT reporter mice, EGFP expression driven via the P2rx7 promoter was evident in SGCs and SCs but was undetectable in SGNs. A second transgenic model showed a comparable cellular distribution of EGFP-tagged P2X7Rs. In wild-type mice the discrete glial expression was confirmed using a P2X7-specific nanobody construct. Our study shows that P2X7Rs are expressed by peripheral glial cells, rather than by afferent neurons. Description of functional signatures and cellular distributions of these enigmatic proteins in the peripheral nervous system (PNS) will help our understanding of ATP-dependent effects contributing to hearing loss and other sensory neuropathies.SIGNIFICANCE STATEMENT P2X7 receptors (P2X7Rs) have been the subject of much scrutiny in recent years. They have been promoted as therapeutic targets in a number of diseases of the nervous system, yet the specific cellular location of these receptors remains the subject of intense debate. In the auditory nerve, connecting the inner ear to the brainstem, we show these multimodal ATP-gated channels localize exclusively to peripheral glial cells rather than the sensory neurons, and are not evident in central glia. Physiologic responses in the peripheral glia display classical hallmarks of P2X7R activation, including the formation of ion-permeable and also macromolecule-permeable pores. These qualities suggest these proteins could contribute to glial-mediated inflammatory processes in the auditory periphery under pathologic disease states.
2016-07-27 | Neural stem/progenitor cell properties of glial cells in the adult mouse auditory nerve.
The auditory nerve is the primary conveyor of hearing information from sensory hair cells to the brain. It has been believed that loss of the auditory nerve is irreversible in the adult mammalian ear, resulting in sensorineural hearing loss. We examined the regenerative potential of the auditory nerve in a mouse model of auditory neuropathy. Following neuronal degeneration, quiescent glial cells converted to an activated state showing a decrease in nuclear chromatin condensation, altered histone deacetylase expression and up-regulation of numerous genes associated with neurogenesis or development. Neurosphere formation assays showed that adult auditory nerves contain neural stem/progenitor cells (NSPs) that were within a Sox2-positive glial population. Production of neurospheres from auditory nerve cells was stimulated by acute neuronal injury and hypoxic conditioning. These results demonstrate that a subset of glial cells in the adult auditory nerve exhibit several characteristics of NSPs and are therefore potential targets for promoting auditory nerve regeneration.
2007-04-05 | Tissue-specific effects of wild-type and mutant connexin 31: a role in neurite outgrowth.
Channels formed by connexins (Cx), the major protein subunits of gap junctions, allow passage of ions and molecular messengers between cells to provide a mechanism of synchronized cellular response. Twenty human Cx isoforms have been identified and mutations in the gene GJB3 encoding the 31 kDa isoform, Cx31, can cause dominant or recessive skin disease, dominant or recessive deafness or dominant neuropathy with deafness. Cx31 is expressed in differentiating keratinocytes in skin. Here, we also demonstrate endogenous Cx31 expression in human neuronal cell lines, particularly in differentiated neurones. Exogenous Cx31 expression induced neurite outgrowth in human neuronal cell lines, but not differentiation in primary human keratinocytes. Though neither the neuropathy and hearing loss mutation (66delD)Cx31 nor the skin disease associated mutation (R42P)Cx31 is able to traffic to the plasma membrane, the R42P mutant induced neurite outgrowth to a level equal to wild-type Cx31. In contrast, there was significantly reduced neurite outgrowth after (66delD)Cx31 expression. In addition to indicating a potential disease mechanism for the neuropathy/deafness mutation, this work demonstrates a tissue-specific function for Cx31.
cell therapies
2026-05-15 | Mesenchymal vs. induced pluripotent stem cells: potential for spiral ganglion neuron regeneration in auditory neuropathy.
Auditory neuropathy is a distinct form of sensorineural hearing loss characterized by dysfunction or degeneration of primary auditory neurons, also known as spiral ganglion neurons (SGNs), which transmit acoustic information from the cochlea to the brain. Increasing evidence indicates that SGNs are particularly susceptible to degeneration induced by noise exposure, ototoxic agents, genetic mutations, or aging, often preceding the loss of cochlear mechanosensory hair cells, and thus represents a critical target for regenerative intervention for auditory neuropathy. Stem cell-based approaches have emerged as promising strategies to restore auditory nerve function. In particular, the generation of otic neuronal progenitors (ONPs) capable of replacing damaged SGNs offers a translationally relevant avenue for therapy. Among candidate sources, mesenchymal stem cells (MSCs) and induced pluripotent stem cells (iPSCs) offer distinct biological and translational advantages. iPSCs provide robust pluripotency and developmental recapitulation capacity, enabling efficient differentiation toward otic neuronal lineages, whereas MSCs offer immunomodulatory properties and paracrine neurotrophic support with lower tumorigenic risk. This mini-review critically compares MSC and iPSC-derived ONPs in terms of differentiation efficiency, neuronal maturation, integration potential, immunogenicity, and scalability. We further discuss emerging complementary strategies, including ONP transplantation, glial cell reprogramming and extracellular vesicle-based therapies. Together, these approaches highlight converging regenerative paradigms aimed at restoring auditory neuron function in neuropathic hearing loss.
2026-01-20 | Evaluating Cochlear Implantation Outcomes in Charcot-Marie-Tooth Disease: A Case Series Analysis of Genetic Profiles and Intervention Timing.
Charcot-Marie-Tooth disease (CMT) is a hereditary neuropathy that may present with sensorineural hearing loss (SNHL) or auditory neuropathy spectrum disorder (ANSD). Cochlear implants (CIs) have been used to rehabilitate hearing loss in CMT, but their effectiveness remains poorly understood due to the central and peripheral neurological complexities of the disease. Clinical capsule report. Two adult CMT patients and 2 pediatric CMT patients. Cochlear implantation. Preoperative clinical profiles and postoperative auditory performance. Case 1: A 60-year-old woman with bilateral ANSD and comorbid multiple sclerosis (MS) achieved significant speech perception improvement (CNC: 8%-68%, AzBio: 64%) 1 year post-CI. Case 2: A 20-month-old boy with GJB1 -associated CMT1X and developmental delays exhibited rapid auditory gains (MLNT: 100%) following CI. Case 3: A 12-year-old boy with AIFM1 -related ANSD and mitochondrial dysfunction achieved moderate speech recognition (CNC: 56%, AzBio: 75%) but remained limited in noisy environments. Case 4: A 32-year-old man with PRPS1 -associated CMTX5 and profound prelingual SNHL showed improved sound awareness (20-30 dB HL) post-CI but had no speech perception gains due to prolonged auditory deprivation. Cochlear implantation in CMT patients demonstrates variable but meaningfully beneficial auditory outcomes, with early intervention yielding the most favorable results. A personalized approach incorporating genetic profiling, tailored rehabilitation strategies, and setting realistic patient expectations is essential to optimizing outcomes.
2025-12-19 | MSC-sEV Promote Regeneration of Cochlear Spiral Ganglion Neurons and Myelin Sheaths in 3D Culture System.
Spiral ganglion neurons (SGNs) play a crucial role in auditory signal transmission, and their degeneration is a significant factor in hearing loss. The protection of SGNs remains a central focus in auditory neuropathy treatment, while repairing their surrounding myelin sheaths has often been underestimated. To better simulate the cochlear neural microenvironment and enhance regenerative therapy, we developed a regenerative strategy using mesenchymal stem cell-derived small extracellular vesicles (MSC-sEV) combined with a biomimetic 3D cochlear culture system. Our results demonstrate that MSC-sEV significantly promotes Schwann cell migration and proliferation, thereby supporting the structural integrity and trophic environment essential for SGN function. Simultaneously, MSC-sEV treatment markedly enhances SGN survival, axonal outgrowth, and neural network reconstruction within the 3D culture model, mimicking the in vivo cochlear microenvironment. Importantly, in an ouabain-induced auditory neuropathy model, MSC-sEV administration attenuated neuronal loss, preserved SGN-hair cell connectivity, and facilitated functional recovery. By targeting both SGNs and their myelin sheaths, this dual-action strategy effectively reconstructs the neuroglial functional unit, fostering a regenerative microenvironment for auditory circuit repair.
2025-12-08 | Neural stem cell-loaded biohybrid hydrogel improves cochlear implants by electrode-neural coupling and neural regeneration.
Background: Contemporary cochlear implants (CIs) face unresolved dual challenges: biomechanical-electrochemical mismatch at the electrode-tissue interface and progressive spiral ganglion neuron (SGN) degeneration, severely limiting long-term auditory restoration. Integrating regenerative medicine with bioelectronic engineering offers promise to overcome these bottlenecks. Methods: A biohybrid neural interface was developed by embedding neural stem cells (NSCs) in photopolymerized poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS)/collagen hydrogel. Physicochemical properties were characterized via rheometry, electron microscopy, and electrochemical impedance spectroscopy. In vitro NSC responses (proliferation/differentiation) were quantified with EdU/Tuj1 assays. Therapeutic efficacy was evaluated in guinea pigs with ouabain-induced auditory neuropathy using auditory brainstem response (ABR) thresholds and immunohistochemical SGN quantification, comparing CI-alone versus NSC-hydrogel-CI groups. Results: The photopolymerized PEDOT:PSS/collagen hydrogel demonstrated cochlear tissue-matched viscoelastic properties (storage modulus: 8.7-12.4 kPa) with injectable sol-gel transition capability, while exhibiting enhanced bioelectronic coupling through high electrical conductivity (1.3 ± 0.1 S/m) and 97.7% reduction in charge transfer resistance. This electroactive microenvironment significantly promoted NSC proliferation (+51.6%) and neuronal differentiation (+76.4%) in vitro, effects further amplified by CI stimulation to achieve +71.5% proliferation and +23.4% neuronal differentiation. In vivo evaluation using ouabain-induced auditory neuropathy guinea pigs revealed substantial functional recovery, with ABR threshold improvements of 18.8-28.8 dB across 4-12 kHz frequencies by post-operative day 14, correlating with significant SGN regeneration in the apical turn (+11.14 cells/0.01 mm²), whereas CI-alone controls exhibited negligible recovery. Conclusions: This NSC-laden conductive hydrogel establishes a self-reinforcing therapeutic paradigm that simultaneously resolves electrode-tissue mismatch through optimized bioelectronic interfacing and reverses neurodegeneration via stem cell-mediated SGN regeneration. The dual-function platform pioneers active neural repair for next-generation neuroprosthetics.
2025-06-04 | A novel BCAP31 variant associated with nonsyndromic auditory neuropathy spectrum disorder: mitochondrial dysfunction, cisplatin sensitivity, and amenability to mitochondrial transplantation.
A novel in-frame insertion variant in the B-Cell Receptor-Associated Protein 31 (BCAP31) gene, which encodes a crucial ER membrane protein involved in the quality control and transport of transmembrane proteins, as well as in ER-mitochondria apoptotic signaling, was determined in a family demonstrating X-linked, recessive, nonsyndromic auditory neuropathy spectrum disorder (ANSD). Exome sequencing analysiswas followed by bioinformatics analysis to identify the cause of hearing loss in a family whose pedigree indicated an X-linked recessive mode of inheritance. Immunohistochemistry was performed to locate Bcap31 in the mouse cochlea. Mitochondrial function was evaluated by measuring intracellular ATP, ROS and mitochondrial membrane potential in control and patient-derived lymphoblastoid cells (LCLs) before and after the administration of mitochondria isolated from human umbilical cord mesenchymal stem cells (UC-MSCs). ANSD observed in our study is characterized by initial inner hair cell damage, followed by accelerated degeneration of cochlear outer hair cells. Functional studies of patient-derived LCLs revealed mitochondrial dysfunction, evidenced by increased ROS, reduced ATP levels, and decreased mitochondrial membrane potential compared with normal LCLs. Further, these cells demonstrated heightened sensitivity to cisplatin-induced apoptosis, as indicated by the increased proapoptotic gene expression. Notably, the administration of mitochondria isolated from umbilical cord mesenchymal stem cells significantly restored mitochondrial dysfunction and alleviated cisplatin-induced cytotoxicity in the patient-derived cells. These results indicate BCAP31 dysfunction as a potential cause of transient ANSD, progressing to sensorineural hearing loss through mitochondrial impairment. Furthermore, they highlighted the therapeutic potential of allogenic mitochondrial transplantation as a novel strategy for treating hearing loss with an underlying component of mitochondrial dysfunction. This study contributes to the understanding of BCAP31's role in auditory neuropathy and mitochondrial health.
gene therapies
2026-04-24 | Auditory neuropathy as the first sign of leptomeningeal metastasis.
Auditory neuropathy is a hearing disorder characterized by impaired temporal coding of acoustic signals in the auditory nerve fibers, resulting in abnormal auditory perceptions relying on temporal cues. We describe the case of a woman with a history of cancer who developed auditory neuropathy as the first manifestation of leptomeningeal metastasis. A woman in her sixties complained of severe difficulties in understanding speech despite preserved sensitivity to sounds, which had begun two months before audiological assessment. Her past medical history was remarkable for an occult cancer, possibly breast cancer, diagnosed seven years earlier. Pure-tone audiometry showed mild bilateral sensorineural hearing loss associated with markedly reduced speech intelligibility. Otoacoustic emissions were normal, indicating preserved outer hair cell function, whereas auditory brainstem responses (ABRs) were absent despite preserved hearing thresholds. Contrast-enhanced brain magnetic resonance imaging (MRI) only demonstrated bilateral enhancement of the eighth cranial nerve. However, a brain MRI performed one month later revealed diffuse leptomeningeal enhancement, while cerebrospinal fluid (CSF) cytology was positive for atypical malignant cells, both findings consistent with leptomeningeal metastasis. This case illustrates that the onset of auditory neuropathy in a patient with a clinical history of cancer may represent an early clinical sign of leptomeningeal metastasis, highlighting the importance of prompt neuroimaging and CSF analysis.
2026-03-01 | Precise and efficient DNA base editing restores normal hearing in adult DFNB9 mouse model.
Mutations in the OTOF gene, which cause autosomal recessive non-syndromic hearing loss, DFNB9, are a leading cause of auditory neuropathy. Gene augmentation and RNA and DNA editing have been used to restore the auditory function of mouse models, and gene augmentation has even been used in patients with DFNB9. However, the therapeutic time window for DFNB9 treatment is largely unknown. We screened multiple adenine base editors to identify an optimal editor for correcting the pathogenic Otof c.2815C>T (p.Gln939∗) mutation. The selected editor was delivered to the cochlea of Otof-deficient mice at different postnatal ages using an adeno-associated-virus-mediated strategy. Auditory function was assessed in the treated Otof-deficient mice, while safety was evaluated in wild-type mice. Nme2ABE8e exhibited superior on-target editing efficiency compared with other base editors. Adeno-associated-virus-mediated delivery of Nme2ABE8e to 1-month-old adult Otof-deficient mice restored auditory function to near-normal levels, with sustained effects for at least 6 months. Importantly, treatment at 2, 3, and 4 months of age also resulted in hearing improvement, indicating an extended therapeutic time window. Comprehensive safety assessments revealed no detectable ototoxicity or neurological deficits. These results underscore the safety and efficacy of Nme2ABE8e for DFNB9 and suggest that patients with DFNB9 may have a relatively long therapeutic time window for gene therapy. This work was funded by the National Key R&D Program of China, the National Natural Science Foundation of China, and other governmental and institutional funding sources.
2026-02-28 | Auditory Neuropathy: Challenges and Significant Progress in Diagnosis and Treatment
ABSTRACT Auditory neuropathy (AN) is a complex disorder where sensorineural hearing impairment occurs due to abnormal neural encoding to sound stimuli. This can be caused by damage to sensory inner hair cells (IHCs)‐presynapse, IHC ribbon synapses, or spiral ganglion neurons via post‐synapse. Genetic factors play a significant role in AN. Audiological assessment such as otoacoustic emissions, auditory brainstem responses, and speech audiometry is crucial in diagnosing auditory neuropathy. Hearing aids and cochlear implants are currently commonly used methods for interventing AN. Owing to the intricate nature of the disease's pathogenesis, a standardized diagnostic approach has yet to be established, and therapeutic options remain significantly constrained. However, it is noteworthy that breakthrough progress has been made in the treatment of AN. In 2024, Chinese researchers used adeno‐associated virus gene therapy for AN patients with OTOF gene mutations, and achieved exceptionally good results in clinical trials. This review focuses on auditory neuropathy, covering its theoretical foundations, epidemiology, diagnostic techniques, treatment strategies, clinical practice, as well as future directions and controversie.
2026-01-21 | A novel minimally invasive stereotaxic technique to target inner ear neurons in the mouse.
Sensorineural hearing loss (SNHL), a leading cause of disability worldwide, arises from damage to hair cells (HCs) or spiral ganglion neurons (SGNs) within the cochlea. Among its etiologies, auditory neuropathy (AN) is characterized by disrupted signal transmission due to SGN damage. Traditional interventions, such as hearing aids and cochlear implants, provide limited benefit in cases of AN, where neuronal damage impairs signal transduction to the brain. Emerging regenerative therapies, including cell replacement and gene delivery, hold potential to restore SGN function, but their application is limited by challenges in delivering therapeutic agents to cochlear targets. In this study, we developed a novel stereotaxic approach for minimally invasive, precise delivery of therapeutic agents to murine SGNs. Utilizing pre-determined coordinates, we successfully accessed the cochlea and SGNs. Immunohistochemistry confirmed accurate delivery and integration of therapeutic agents. Functional hearing assessments showed that the approach preserved HC function and demonstrated minimal adverse effects. This technique offers a scalable platform for advancing cell and gene therapies aimed at restoring auditory function in AN and other forms of SNHL.
2025-11-14 | Characteristic cortical alterations in auditory neuropathy: An EEG study.
Auditory neuropathy (AN) is a complex auditory disorder characterized by disproportionately poor speech discrimination despite preserved auditory sensitivity, substantially impacting daily communication and overall quality of life. This study conducted comprehensive audiological measurements and high-density electroencephalography (EEG) measurements in resting and auditory task states on 21 AN, 21 age-, gender-, and hearing threshold-matched sensorineural hearing loss (SNHL), and 21 age- and gender-matched normal hearing (NH) subjects. The topological network attributes, microstates, event-related potentials (ERP), cortical lateralization, phase-locking value (PLV) functional connectivity strength of EEG, and correlations with audiological indicators were compared among three groups. The results showed that in the resting state, the global field power (GFP) of microstate A differed significantly after FDR correction, with SNHL showing higher GFP 3.23 (2.46-3.93) μV than AN 2.37 (2.08-3.08) μV and NH 2.38 (2.08-2.63) μV. The transition probability (TP) from microstate A to B and from B to C were higher in SNHL than NH (both P after correction = 0.011). During task processing, N1 amplitude was lower in SNHL than NH (P after correction = 0.023), while N1 latency was shorter in AN than SNHL (P after correction = 0.006) and was correlated with low-frequency PTA (correlation coefficient = 0.362, P after correction = 0.020). AN additionally exhibited left-hemispheric lateralization (P after correction < 0.05). Source localization revealed greater cortical activation in SNHL than in AN and NH, predominantly in the superior frontal gyrus (SNHL > NH: P = 0.00020, t0.05 = 3.692, and SNHL > AN: P = 0.01140, t0.05 = -3.794). Collectively, these findings demonstrate that AN exhibits unique neural compensation patterns distinct from SNHL, supporting cortical reorganization mechanisms specific to neural dyssynchrony rather than simple auditory input reduction.
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