RARE DISEASE
Non-syndromic genetic deafness
Non-syndromic genetic deafness
Non-syndromic genetic deafness
Synonyms: Isolated genetic deafness, Isolated genetic hearing loss, Non-syndromic genetic hearing loss
Synonyms: Isolated genetic deafness, Isolated genetic hearing loss, Non-syndromic genetic hearing loss
Synonyms: Isolated genetic deafness, Isolated genetic hearing loss, Non-syndromic genetic hearing loss
Drug discovery
8
drugs
With orphan designations
Overview
Non-syndromic genetic deafness is the most common hereditary hearing disorder, characterized by isolated sensorineural hearing loss without associated systemic features. It accounts for ~70% of genetic hearing loss cases, primarily caused by mutations in genes like GJB2 (connexin 26) and SLC26A4. Inheritance patterns include autosomal recessive (75-80%), dominant (20-25%), X-linked (1-2%), and mitochondrial (<1%) [1][2][6]. Severity ranges from mild to profound, often presenting prelingually [14].
Burden
Major contributor to childhood disability, impacting speech development, education, and socioeconomic outcomes [9]. Annual global economic burden exceeds $750 billion, with suboptimal outcomes in 30% of cochlear implant recipients [8][16]. Early genetic diagnosis via newborn screening improves intervention timing [9].
Categories: rare genetic diseases, rare otorhinolaryngological diseases
Research Papers
241 drug discovery papers about Non-syndromic genetic deafness, with 1 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
241 drug discovery papers about Non-syndromic genetic deafness, with 1 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-08-14 | The ZBTB16/CUL3/ROC1 ubiquitin ligase drives the degradation of pathogenic pendrin (SLC26A4) protein variants.
Pathogenic sequence alterations in the SLC26A4 gene, which encodes the solute carrier SLC26A4/pendrin, lead to Pendred syndrome and non-syndromic autosomal recessive deafness type B4 (DFNB4), two of the most common forms of hearing loss worldwide. Many pathogenic SLC26A4 protein variants exhibit reduced cellular levels due to ubiquitin-proteasome system (UPS)-mediated degradation, and UPS inhibition rescues their plasma membrane expression and ion transport function. However, the underlying molecular mechanisms remain unclear and may involve interactions with novel molecular partners. A candidate SLC26A4 protein partner was found by a yeast two-hybrid screening. The biological significance of this interaction has been studied by immunohistochemistry and co-localization in the mouse inner ear and kidney, co-immunoprecipitation of endogenous and recombinant proteins, Liquid Chromatography-Tandem Mass Spectrometry, and Fluorescence Resonance Energy Transfer. We identified the zinc finger and BTB domain-containing protein ZBTB16 as a novel SLC26A4-interacting partner. ZBTB16 co-localized with SLC26A4 in the outer sulcus and spiral prominence epithelial cells of the mouse cochlea and in the apical membrane of non-alpha non-beta intercalated cells of the distal nephron. ZBTB16 was found to be part of a ubiquitin-ligase complex comprising the scaffold protein Cullin 3 and the ubiquitin ligase RocI, and to bind with its C-terminal zinc finger region a unique amino acid sequence within the C-terminal Sulfate Transporter and Anti-Sigma factor Antagonist (STAS) domain of SLC26A4. This direct molecular interaction leads to increased site- and variant-specific ubiquitination and accelerated degradation of SLC26A4. Finally, using AI-based structure prediction, we provide an atomistic model of the complete SLC26A4/ZBTB16/Cullin 3/RocI complex in agreement with our experimental results. These findings describe a primary mechanism of SLC26A4 regulation in the inner ear and kidney and of SLC26A4 loss of function in Pendred syndrome and deafness DFNB4, and identify potential novel molecular targets for therapeutic intervention.
2026-07-20 | Patient-Derived Inner Ear Organoids as a Disease Modeling and Therapy Validation Platform For Hereditary Inner Ear Disorders
Abstract Background Hereditary inner ear disorders comprise a highly heterogenous group of disorders and are a major cause of hearing and vestibular dysfunction. Despite advances in genetic diagnosis, the development of precision therapies has been limited by the lack of relevant and scalable human model systems that can accommodate the wide spectrum of disease-causing variants and support the evaluation of therapeutic interventions. We established patient-derived inner ear organoids (IEOs) as a platform to assess antisense oligonucleotide (ASO)-based therapeutic strategies for hereditary hearing loss. Methods Two representative genetic models were selected: recessive syndromic Usher syndrome type IIa ( USH2A ) and dominant non-syndromic DFNA9 ( COCH ). Human induced pluripotent stem cells (iPSCs) were generated from a patient carrying a homozygous pathogenic USH2A variant and a patient carrying a frequently occurring pathogenic COCH variant. In parallel, isogenic iPSC lines were created by introducing the same disease-causing variants into a healthy donor background. Following differentiation into IEOs, disease-associated transcript expression was evaluated. Splice-switching and RNase H1-mediated gapmer ASOs were assessed for target engagement. ASO biodistribution and cellular uptake was also examined in both IEOs and adult human vestibular tissue. Results Patient-derived and isogenic iPSCs were successfully differentiated into IEOs that recapitulated disease-associated transcript expression. ASOs showed efficient uptake into disease-relevant cell populations in both IEOs and adult human vestibular tissue. In USH2A -variant IEOs, splice-switching ASO treatment corrected aberrant splicing. In COCH -variant IEOs, gapmer ASO treatment reduced total COCH transcript levels, achieving up to 75% knockdown in patient-derived IEOs. Conclusions Patient-derived and isogenic variant IEOs provide a versatile and scalable human platform for evaluating ASO therapies for hereditary hearing loss. Their adaptability to diverse genetic variants, inheritance patterns, and ASO modalities makes them well suited to address the genetic heterogeneity of hereditary inner ear diseases and establishes IEOs as a broadly applicable preclinical model for rare hereditary inner ear diseases.
2026-06-09 | Quinazoline alleviates inner ear damage by enhancing the proliferation and differentiation of neural stem cells.
Neural stem cell (NSC) transplantation exerts therapeutic effects on inner ear damage and pretreatment with quinazoline compounds may further enhance this efficacy. This study aimed to investigate whether quinazoline alleviates inner ear damage by enhancing the proliferation and differentiation of NSCs. Forty Hartley guinea pigs were randomly assigned to four groups. Hippocampal NSCs isolated from neonatal guinea pigs were pretreated with quinazoline and transplanted into animals with cisplatin-induced hearing loss. Evaluations included NSC proliferation and differentiation, auditory brainstem response (ABR) thresholds and miR-183 expression in cochlear tissues. Quinazoline pretreatment significantly enhanced NSC proliferation and differentiation (P<0.05). After transplantation, the group receiving quinazoline-pretreated NSCs showed a significantly lower ABR threshold (reflecting an approximately 10 dB improvement in hearing recovery) than the group receiving untreated NSCs (P<0.05). This was accompanied by more pronounced structural repair of the cochlea and a significant upregulation of miR-183 expression (P<0.05). Quinazoline promotes the repair of inner ear injury by enhancing the proliferation and differentiation of NSCs, a mechanism that appears to be associated with the upregulation of miR-183 expression.
2026-06-04 | Tonotopic specialization of MYO7A isoforms in auditory hair cells.
Mutations in Myo7a cause Usher syndrome type 1B and non-syndromic deafness, but the precise function of MYO7A in sensory hair cells remains unclear. Using long-read sequencing, we identify and characterize a novel isoform, MYO7A-N, expressed in auditory hair cells alongside the canonical MYO7A-C. Isoform-specific knock-in mouse models reveal that inner hair cells primarily express MYO7A-C, while outer hair cells express both isoforms in opposing tonotopic gradients. Both isoforms are localized to the upper tip-link insertion site, consistent with a role in the tip link for mechanotransduction. Loss of MYO7A-N leads to outer hair cell degeneration and progressive hearing loss. Cryo-EM structures reveal isoform-specific differences at actomyosin interfaces, correlating with distinct ATPase activities. These findings reveal an unexpected layer of molecular diversity within the mechanotransduction machinery. We propose that MYO7A isoform specialization enables fine-tuning of tip-link tension, thus hearing sensitivity, and contributes to the frequency-resolving power of the cochlea.
2026-05-30 | Mouse models and translational research progress of hereditary vestibular dysfunction.
BackgroundHereditary vestibular dysfunctions (HVDs) are a group of diseases caused by genetic mutations, characterized by congenital or progressive vestibular dysfunction, often accompanied by hearing loss or other systemic damages. These diseases are divided into syndromic (e.g., Usher syndrome, CHARGE syndrome) and non-syndromic types, involving mutations in key genes such as MYO7A, COCH, SLC26A4, TMC1, etc. Although clinical phenotypes vary, the pathogenesis is complex, traditional diagnostic methods are limited, and effective treatments are lacking. Mouse models are important tools for studying hereditary vestibular dysfunction, providing critical platforms for understanding disease mechanisms, developing diagnostic biomarkers, and treatment strategies.MethodsThis review systematically searched English and Chinese literature in databases including PubMed, Web of Science, Embase, and CNKI from January 2000 to April 2026. The search strategy combined Medical Subject Headings (MeSH) terms and free-text keywords, including "hereditary vestibular dysfunction," "mouse models," "gene therapy," "CRISPR-Cas9," "Usher syndrome," "translational research," "biomarkers," "Meniere disease," and "International Mouse Phenotyping Consortium." Inclusion criteria were: (1) peer-reviewed articles on hereditary vestibular dysfunction mouse models; (2) studies reporting genetic mechanisms, pathophysiology, or therapeutic interventions; and (3) English or Chinese language publications. Exclusion criteria were: (1) non-peer-reviewed conference abstracts or preprints and (2) studies without clear genetic or phenotypic characterization. Two authors independently screened titles, abstracts, and full texts, with disagreements resolved by consensus. The review focuses on analyzing the applications of spontaneous mutation models, genetic engineering models, CRISPR technology-based models, and knockout models from the International Mouse Phenotype Consortium (IMPC) in disease mechanism research and treatment development.ResultsIn recent years, significant progress has been made in hereditary vestibular dysfunction mouse model research. Spontaneous mutation models like Myo6 and Cdh23 mutant mice have revealed the key role of cytoskeletal and cell junctions in vestibular function. Genetic engineering models have successfully simulated a variety of diseases, including Usher syndrome, ion channel defects, and vestibular development abnormalities, elucidating the molecular mechanisms of TMC1/2 mechanosensory channels, SLC26A4 ion transport, and vestibular system development genes. The application of CRISPR-Cas9 technology has greatly improved model construction efficiency and precision. These models have shown positive results in gene therapy, gene editing, and drug treatment research. AAV-mediated gene replacement therapy, CRISPR gene repair, and new drugs such as α1-antitrypsin have all achieved positive outcomes in mouse models. Biomarker studies based on multi-omics techniques have identified potential diagnostic markers such as Slc17a6 and BDNF.ConclusionMouse models play an irreplaceable role in the study of hereditary vestibular dysfunction, providing a solid foundation for elucidating disease mechanisms, improving diagnostic methods, and developing treatment strategies. Although clinical translation still faces challenges such as species differences, delivery efficiency, and treatment windows, with the continuous development of gene editing technology, nano-delivery systems, and multi-omics techniques, personalized diagnosis and treatment for hereditary vestibular dysfunction are expected to be realized, bringing new hope to patients.
2026-08-14 | The ZBTB16/CUL3/ROC1 ubiquitin ligase drives the degradation of pathogenic pendrin (SLC26A4) protein variants.
Pathogenic sequence alterations in the SLC26A4 gene, which encodes the solute carrier SLC26A4/pendrin, lead to Pendred syndrome and non-syndromic autosomal recessive deafness type B4 (DFNB4), two of the most common forms of hearing loss worldwide. Many pathogenic SLC26A4 protein variants exhibit reduced cellular levels due to ubiquitin-proteasome system (UPS)-mediated degradation, and UPS inhibition rescues their plasma membrane expression and ion transport function. However, the underlying molecular mechanisms remain unclear and may involve interactions with novel molecular partners. A candidate SLC26A4 protein partner was found by a yeast two-hybrid screening. The biological significance of this interaction has been studied by immunohistochemistry and co-localization in the mouse inner ear and kidney, co-immunoprecipitation of endogenous and recombinant proteins, Liquid Chromatography-Tandem Mass Spectrometry, and Fluorescence Resonance Energy Transfer. We identified the zinc finger and BTB domain-containing protein ZBTB16 as a novel SLC26A4-interacting partner. ZBTB16 co-localized with SLC26A4 in the outer sulcus and spiral prominence epithelial cells of the mouse cochlea and in the apical membrane of non-alpha non-beta intercalated cells of the distal nephron. ZBTB16 was found to be part of a ubiquitin-ligase complex comprising the scaffold protein Cullin 3 and the ubiquitin ligase RocI, and to bind with its C-terminal zinc finger region a unique amino acid sequence within the C-terminal Sulfate Transporter and Anti-Sigma factor Antagonist (STAS) domain of SLC26A4. This direct molecular interaction leads to increased site- and variant-specific ubiquitination and accelerated degradation of SLC26A4. Finally, using AI-based structure prediction, we provide an atomistic model of the complete SLC26A4/ZBTB16/Cullin 3/RocI complex in agreement with our experimental results. These findings describe a primary mechanism of SLC26A4 regulation in the inner ear and kidney and of SLC26A4 loss of function in Pendred syndrome and deafness DFNB4, and identify potential novel molecular targets for therapeutic intervention.
2026-07-20 | Patient-Derived Inner Ear Organoids as a Disease Modeling and Therapy Validation Platform For Hereditary Inner Ear Disorders
Abstract Background Hereditary inner ear disorders comprise a highly heterogenous group of disorders and are a major cause of hearing and vestibular dysfunction. Despite advances in genetic diagnosis, the development of precision therapies has been limited by the lack of relevant and scalable human model systems that can accommodate the wide spectrum of disease-causing variants and support the evaluation of therapeutic interventions. We established patient-derived inner ear organoids (IEOs) as a platform to assess antisense oligonucleotide (ASO)-based therapeutic strategies for hereditary hearing loss. Methods Two representative genetic models were selected: recessive syndromic Usher syndrome type IIa ( USH2A ) and dominant non-syndromic DFNA9 ( COCH ). Human induced pluripotent stem cells (iPSCs) were generated from a patient carrying a homozygous pathogenic USH2A variant and a patient carrying a frequently occurring pathogenic COCH variant. In parallel, isogenic iPSC lines were created by introducing the same disease-causing variants into a healthy donor background. Following differentiation into IEOs, disease-associated transcript expression was evaluated. Splice-switching and RNase H1-mediated gapmer ASOs were assessed for target engagement. ASO biodistribution and cellular uptake was also examined in both IEOs and adult human vestibular tissue. Results Patient-derived and isogenic iPSCs were successfully differentiated into IEOs that recapitulated disease-associated transcript expression. ASOs showed efficient uptake into disease-relevant cell populations in both IEOs and adult human vestibular tissue. In USH2A -variant IEOs, splice-switching ASO treatment corrected aberrant splicing. In COCH -variant IEOs, gapmer ASO treatment reduced total COCH transcript levels, achieving up to 75% knockdown in patient-derived IEOs. Conclusions Patient-derived and isogenic variant IEOs provide a versatile and scalable human platform for evaluating ASO therapies for hereditary hearing loss. Their adaptability to diverse genetic variants, inheritance patterns, and ASO modalities makes them well suited to address the genetic heterogeneity of hereditary inner ear diseases and establishes IEOs as a broadly applicable preclinical model for rare hereditary inner ear diseases.
2026-06-09 | Quinazoline alleviates inner ear damage by enhancing the proliferation and differentiation of neural stem cells.
Neural stem cell (NSC) transplantation exerts therapeutic effects on inner ear damage and pretreatment with quinazoline compounds may further enhance this efficacy. This study aimed to investigate whether quinazoline alleviates inner ear damage by enhancing the proliferation and differentiation of NSCs. Forty Hartley guinea pigs were randomly assigned to four groups. Hippocampal NSCs isolated from neonatal guinea pigs were pretreated with quinazoline and transplanted into animals with cisplatin-induced hearing loss. Evaluations included NSC proliferation and differentiation, auditory brainstem response (ABR) thresholds and miR-183 expression in cochlear tissues. Quinazoline pretreatment significantly enhanced NSC proliferation and differentiation (P<0.05). After transplantation, the group receiving quinazoline-pretreated NSCs showed a significantly lower ABR threshold (reflecting an approximately 10 dB improvement in hearing recovery) than the group receiving untreated NSCs (P<0.05). This was accompanied by more pronounced structural repair of the cochlea and a significant upregulation of miR-183 expression (P<0.05). Quinazoline promotes the repair of inner ear injury by enhancing the proliferation and differentiation of NSCs, a mechanism that appears to be associated with the upregulation of miR-183 expression.
2026-06-04 | Tonotopic specialization of MYO7A isoforms in auditory hair cells.
Mutations in Myo7a cause Usher syndrome type 1B and non-syndromic deafness, but the precise function of MYO7A in sensory hair cells remains unclear. Using long-read sequencing, we identify and characterize a novel isoform, MYO7A-N, expressed in auditory hair cells alongside the canonical MYO7A-C. Isoform-specific knock-in mouse models reveal that inner hair cells primarily express MYO7A-C, while outer hair cells express both isoforms in opposing tonotopic gradients. Both isoforms are localized to the upper tip-link insertion site, consistent with a role in the tip link for mechanotransduction. Loss of MYO7A-N leads to outer hair cell degeneration and progressive hearing loss. Cryo-EM structures reveal isoform-specific differences at actomyosin interfaces, correlating with distinct ATPase activities. These findings reveal an unexpected layer of molecular diversity within the mechanotransduction machinery. We propose that MYO7A isoform specialization enables fine-tuning of tip-link tension, thus hearing sensitivity, and contributes to the frequency-resolving power of the cochlea.
2026-05-30 | Mouse models and translational research progress of hereditary vestibular dysfunction.
BackgroundHereditary vestibular dysfunctions (HVDs) are a group of diseases caused by genetic mutations, characterized by congenital or progressive vestibular dysfunction, often accompanied by hearing loss or other systemic damages. These diseases are divided into syndromic (e.g., Usher syndrome, CHARGE syndrome) and non-syndromic types, involving mutations in key genes such as MYO7A, COCH, SLC26A4, TMC1, etc. Although clinical phenotypes vary, the pathogenesis is complex, traditional diagnostic methods are limited, and effective treatments are lacking. Mouse models are important tools for studying hereditary vestibular dysfunction, providing critical platforms for understanding disease mechanisms, developing diagnostic biomarkers, and treatment strategies.MethodsThis review systematically searched English and Chinese literature in databases including PubMed, Web of Science, Embase, and CNKI from January 2000 to April 2026. The search strategy combined Medical Subject Headings (MeSH) terms and free-text keywords, including "hereditary vestibular dysfunction," "mouse models," "gene therapy," "CRISPR-Cas9," "Usher syndrome," "translational research," "biomarkers," "Meniere disease," and "International Mouse Phenotyping Consortium." Inclusion criteria were: (1) peer-reviewed articles on hereditary vestibular dysfunction mouse models; (2) studies reporting genetic mechanisms, pathophysiology, or therapeutic interventions; and (3) English or Chinese language publications. Exclusion criteria were: (1) non-peer-reviewed conference abstracts or preprints and (2) studies without clear genetic or phenotypic characterization. Two authors independently screened titles, abstracts, and full texts, with disagreements resolved by consensus. The review focuses on analyzing the applications of spontaneous mutation models, genetic engineering models, CRISPR technology-based models, and knockout models from the International Mouse Phenotype Consortium (IMPC) in disease mechanism research and treatment development.ResultsIn recent years, significant progress has been made in hereditary vestibular dysfunction mouse model research. Spontaneous mutation models like Myo6 and Cdh23 mutant mice have revealed the key role of cytoskeletal and cell junctions in vestibular function. Genetic engineering models have successfully simulated a variety of diseases, including Usher syndrome, ion channel defects, and vestibular development abnormalities, elucidating the molecular mechanisms of TMC1/2 mechanosensory channels, SLC26A4 ion transport, and vestibular system development genes. The application of CRISPR-Cas9 technology has greatly improved model construction efficiency and precision. These models have shown positive results in gene therapy, gene editing, and drug treatment research. AAV-mediated gene replacement therapy, CRISPR gene repair, and new drugs such as α1-antitrypsin have all achieved positive outcomes in mouse models. Biomarker studies based on multi-omics techniques have identified potential diagnostic markers such as Slc17a6 and BDNF.ConclusionMouse models play an irreplaceable role in the study of hereditary vestibular dysfunction, providing a solid foundation for elucidating disease mechanisms, improving diagnostic methods, and developing treatment strategies. Although clinical translation still faces challenges such as species differences, delivery efficiency, and treatment windows, with the continuous development of gene editing technology, nano-delivery systems, and multi-omics techniques, personalized diagnosis and treatment for hereditary vestibular dysfunction are expected to be realized, bringing new hope to patients.
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Drug Discovery Landscape
8 orphan drug designations for Non-syndromic genetic deafness, including 1 approved therapy.
8 orphan drug designations for Non-syndromic genetic deafness, including 1 approved therapy.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
dual vector gene therapy product containing recombinant adeno-associated viral vector serotype expressing full human OTOF protein | gene therapies | FDA | 2024-08-06 | — | Suzhou Otovia Therapeutics Co., Ltd. |
Dual recombinant adeno-associated viral vectors encoding the human otoferlin gene | gene therapies | FDA | 2023-12-21 | — | Shanghai Refreshgene Therapeutics Co., Ltd. |
Adeno-associated viral vector serotype 1 containing the 3' portion of human OTOF gene, adeno-associated viral vector serotype 1 containing the 5' portion of human OTOF gene | gene therapies | EMA | 2023-03-20 | — | Regeneron Ireland Designated Activity Company |
A dual vector gene therapy product containing AAV8 vectors expressing the 5¿ and 3¿ portion of human otoferlin (OTOF) gene | gene therapies | FDA | 2022-11-29 | — | Sensorion S.A. |
Adeno‐associated viral vector serotype 8 containing the 3' human otoferlin coding sequence, adeno‐associated viral vector serotype 8 containing the 5' human otoferlin coding sequence | gene therapies | EMA | 2022-10-11 | — | Sensorion |
lunsotogene parvec-cwha [Otarmeni] | gene therapies | FDA | 2021-08-11 | 2026-04-23 | Regeneron Pharmaceuticals, Inc. |
Adeno-associated viral vector serotype Anc80 containing the 3' portion of human OTOF gene, adeno-associated viral vector serotype Anc80 containing the 5' portion of human OTOF gene | gene therapies | EMA | 2021-07-19 | — | Eli Lilly Nederland B.V. |
A recombinant adeno-associated viral (AAV) vector encoding the human otoferlin (hOTOF) gene. | gene therapies | FDA | 2021-04-12 | — | Akouos, Inc. |
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