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Adeno-associated virus (AAV) has been successfully used to deliver gene therapy to improve auditory function in mouse models of hereditary hearing loss. Many forms of hereditary hearing loss have mutations which affect the cochlear hair cells, the mechanosensory cells which allow for sound detection and processing. While most conventional AAVs infect inner hair cells (IHCs) with various efficiencies, they infect outer hair cells (OHCs) and supporting cells at lower levels in the cochlea. Here we examine the infection patterns of two synthetic AAVs (AAV2.7m8 and AAV8BP2) in the mouse inner ear. AAV2.7m8 infects both IHCs and OHCs with high efficiency. In addition, AAV2.7m8 infects inner pillar cells and inner phalangeal cells with high efficiency. Our results suggest that AAV2.7m8 is an excellent viral vector for inner ear gene therapy targeting cochlear hair cells and supporting cells, and it will likely greatly expand the potential applications for inner ear gene therapy. Adeno-associated virus is used in gene therapy in mouse models of hearing loss. Here the authors compare vectors and find AAV2.7m8 can infect cells in the inner ear with high efficiency.

Sudden sensorineural hearing loss (SSNHL) is a medical emergency, making detailed examination to determine possible causes and early treatment important. However, etiological examinations in SSNHL do not always reveal a cause, and several factors have been found to affect treatment outcomes. Various studies are being performed to determine the prognosis and effects of treatment in patients who experience sudden hearing loss, and to identify biomarkers associated with this condition. Embase, PubMed, and the Cochrane database were searched using the key words SSNHL, prognostic, and biomarker. This search identified 4 articles in Embase, 28 articles in PubMed, and 36 in the Cochrane database. Of these 68 articles, 3 were duplicates and 37 were unrelated to the research topic. After excluding these articles, the remaining 28 articles were reviewed. Factors associated with SSNHL were divided into six categories: metabolic, hemostatic, inflammatory, immunologic, oxidative, and other factors. The associations between these factors with the occurrence of SSNHL and with patient prognosis were analyzed. Low monocyte counts, low neutrophil/lymphocyte ratio (NLR) and monocyte/high-density lipoproteins (HDL) cholesterol ratio (MHR), and low concentrations of fibrinogen, platelet glycoprotein (GP) IIIa, and TNF-α were found to be associated with good prognosis. However, these factors alone could not completely determine the onset of and recovery from SSNHL, suggesting the need for future basic and clinical studies.

Hearing is essential for communication, and its loss can cause a serious disruption to one’s social life. Hearing loss is also recognized as a major risk factor for dementia; therefore, addressing hearing loss is a pressing global issue. Sensorineural hearing loss, the predominant type of hearing loss, is mainly due to damage to the inner ear along with a variety of pathologies including ischemia, noise, trauma, aging, and ototoxic drugs. In addition to genetic factors, oxidative stress has been identified as a common mechanism underlying several cochlear pathologies. The cochlea, which plays a major role in auditory function, requires high-energy metabolism and is, therefore, highly susceptible to oxidative stress, particularly in the mitochondria. Based on these pathological findings, the potential of antioxidants for the treatment of hearing loss has been demonstrated in several animal studies. However, results from human studies are insufficient, and future clinical trials are required. This review discusses the relationship between sensorineural hearing loss and reactive oxidative species (ROS), with particular emphasis on age-related hearing loss, noise-induced hearing loss, and ischemia–reperfusion injury. Based on these mechanisms, the current status and future perspectives of ROS-targeted therapy for sensorineural hearing loss are described.

Mutations of coding regions and splice sites of SLC26A4 cause Pendred syndrome and nonsyndromic recessive hearing loss DFNB4. SLC26A4 encodes pendrin, a transmembrane exchanger of anions and bases. The mutant SLC26A4 phenotype is characterized by inner ear malformations, including an enlarged vestibular aqueduct (EVA), incomplete cochlear partition type II and modiolar hypoplasia, progressive and fluctuating hearing loss, and vestibular dysfunction. A thyroid iodine organification defect can lead to multinodular goiter and distinguishes Pendred syndrome from DFNB4. Pendred syndrome and DFNB4 are each inherited as an autosomal recessive trait caused by biallelic mutations of SLC26A4 (M2). However, there are some EVA patients with only one detectable mutant allele (M1) of SLC26A4. In most European-Caucasian M1 patients, there is a haplotype that consists of 12 variants upstream of SLC26A4, called CEVA (Caucasian EVA), which acts as a pathogenic recessive allele in trans to mutations affecting the coding regions or splice sites of SLC26A4. This combination of an M1 genotype with the CEVA haplotype is associated with a less severe phenotype than the M2 genotype. The phenotype in EVA patients with no mutant alleles of SLC26A4 (M0) has a very low recurrence probability and is likely to be caused by other factors.

Cochlear homeostasis is critical for the preservation of hearing sensitivity by maintaining optimal cochlear fluid composition, sustaining electrochemical gradients, and supporting the function of sensory and supporting cells in the cochlea. Sensorineural hearing loss, resulting from the damage or loss of sensory hair cells, auditory neurons and other cochlear cells and structures, is intimately linked to disruptions in the homeostatic environment. In this narrative review, we explore the cellular and molecular pathways underpinning cochlear homeostasis in health and disease and examine the mechanisms by which failed homeostasis leads to sensorineural hearing loss. We further discuss current research avenues and emerging therapeutic strategies to restore or compensate for the loss of homeostatic balance. These interventions suggest a future where regenerative healing is possible, ultimately leading to permanent repair and functional recovery.

Premature ovarian insufficiency (POI) affects 1 in 100 women and is a leading cause of female infertility. There are over 80 genes in which variants can cause POI, with these explaining only a minority of cases. Whole exome sequencing (WES) can be a useful tool for POI patient management, allowing clinical care to be personalized to underlying cause. We performed WES to investigate two French sisters, whose only clinical complaint was POI. Surprisingly, they shared one known and one novel likely pathogenic variant in the Perrault syndrome gene, LARS2. Using amino-acylation studies, we established that the novel missense variant significantly impairs LARS2 function. Perrault syndrome is characterized by sensorineural hearing loss in addition to POI. This molecular diagnosis alerted the sisters to the significance of their difficulty in following conversation. Subsequent audiology assessment revealed a mild bilateral hearing loss. We describe the first cases presenting with perceived isolated POI and causative variants in a Perrault syndrome gene. Our study expands the phenotypic spectrum associated with LARS2 variants and highlights the clinical benefit of having a genetic diagnosis, with prediction of potential co-morbidity and prompt and appropriate medical care, in this case by an audiologist for early detection of hearing loss.

Sensorineural hearing loss (SNHL) is significantly more prevalent in individuals with chronic kidney disease (CKD) than in the general population. Although a strong independent association has been observed between kidney dysfunction and the risk of hearing loss, the underlying mechanisms linking these conditions remain poorly understood. This study investigated the pathophysiology of hearing impairment using adriamycin nephropathy (AN), a well-established animal model of CKD. AN was induced in male BALB/c mice using 10 or 12 mg/kg of adriamycin (ADR), resulting in severe kidney injury and concurrent hearing loss. ADR-treated mice exhibited significant glomerular injury, podocyte damage, and elevated renal neutrophil gelatinase-associated lipocalin (NGAL), along with increased serum creatinine and blood urea nitrogen levels. Hearing impairment was evident after 4–8 weeks of ADR treatment, as assessed by auditory brainstem response and distortion-product otoacoustic emissions, and was accompanied by cochlear hair cell loss and ribbon synapse degeneration. AN affected cochlear function by altering ion channel expression in the stria vascularis and inducing blood–labyrinth barrier (BLB) hyperpermeability, along with changes in endothelial cells, pericytes, and perivascular-resident macrophage-like melanocytes. AN significantly increased cochlear NGAL and NLRP3 levels at 4 and 8 weeks following ADR administration. NGAL was highly expressed in the tectorial membrane, cochlear neurons, and organ of Corti, while its receptor, 24p3R, was co-localized with NGAL. These findings demonstrated the role of NGAL and BLB disruption in ADR-induced SNHL, providing novel insights into the mechanistic link between CKD and hearing loss.

Activating transcription factor 6 (ATF6) is a key regulator of the unfolded protein response (UPR) and is important for ER function and protein homeostasis in metazoan cells. Patients carrying loss-of-function ATF6 disease alleles develop the cone dysfunction disorder achromatopsia. The effect of loss of ATF6 function on other cell types, organs, and diseases in people remains unclear. Here, we report that progressive sensorineural hearing loss was a notable complaint in some patients carrying ATF6 disease alleles and that Atf6-/- mice also showed progressive auditory deficits affecting both sexes. In mice with hearing deficits, we found disorganized stereocilia on hair cells and focal loss of outer hair cells. Transcriptomics analysis of Atf6-/- cochleae revealed a marked induction of the UPR, especially through the protein kinase RNA-like endoplasmic reticulum kinase (PERK) arm. These findings identify ATF6 as an essential regulator of cochlear health and function. Furthermore, they support the idea that ATF6 inactivation in people causes progressive sensorineural hearing loss as part of a blindness-deafness genetic syndrome targeting hair cells and cone photoreceptors. Last, our genetic findings indicate that ER stress is an important pathomechanism underlying cochlear damage and hearing loss, with clinical implications for patient lifestyle modifications that minimize environmental and physiological sources of ER stress to the ear.

Hearing loss profoundly affects social engagement, mental health, cognition, and brain development, with sensorineural hearing loss (SNHL) being a major concern. Linked to ototoxic medications, ageing, and noise exposure, SNHL presents significant treatment challenges, highlighting the need for effective prevention and regeneration strategies. Ferroptosis, a distinct form of cell death featuring iron-dependent lipid peroxidation, has garnered interest due to its potential role in cancer, ageing, and neuronal degeneration, especially hearing loss. The emerging role of ferroptosis as a crucial mediator in SNHL suggests that it may offer a novel therapeutic target for otoprotection. This review aims to summarise the intricate connection between ferroptosis and SNHL, offering a fresh perspective for exploring targeted therapeutic strategies that could potentially mitigate cochlear cells damage and enhance the quality of life for individuals with hearing impairments.

Background Inflammation is a principal cause of sensorineural hearing loss resulting from cochlear injury. However, current research investigating the mechanisms of sensorineural inflammatory injury remains inadequate. Methods Cochlear inflammation was induced by administering lipopolysaccharide (LPS) into the otic bulla (OB) and posterior semicircular canal (PSCC). Auditory brainstem responses (ABR) were recorded, and cochlear tissue alterations were analyzed using hematoxylin and eosin (HE) staining and immunofluorescence. Levels of cochlear inflammation were quantified using a cytokine array. Additionally, Toll-like receptor 4 (TLR4) knockout mice were employed to evaluate sensorineural neuroprotection. Results LPS injection into the PSCC caused more pronounced and stable cochlear inflammatory damage compared to injection into the OB. LPS exposure led to significant loss of cochlear hair cells, atrophy of the stria vascularis, and spiral ganglion damage. Furthermore, LPS treatment upregulated TLR4 receptor expression, increased the number of Ionized calcium-binding adapter molecule 1 (IBA1) positive cells, and elevated levels of inflammatory cytokines in the cochlea. TLR4 knockout (TLR4-KO) mice demonstrated reduced LPS-induced cochlear sensorineural damage. Conclusion LPS injection into the PSCC induces sensorineural tissue damage in the cochlea and results in sensorineural hearing loss. These findings suggest that TLR4 inhibition can alleviate cochlear inflammation-induced sensorineural hearing loss. TLR4 represents a potential therapeutic target for sensorineural hearing loss.