RARE DISEASE
Usher syndrome
Usher syndrome
Usher syndrome
Synonyms: Retinitis pigmentosa-deafness syndrome, Retinitis pigmentosa-hearing loss syndrome, USH
Synonyms: Retinitis pigmentosa-deafness syndrome, Retinitis pigmentosa-hearing loss syndrome, USH
Synonyms: Retinitis pigmentosa-deafness syndrome, Retinitis pigmentosa-hearing loss syndrome, USH
Drug discovery
4
drugs
With orphan designations
Overview
Usher syndrome is an autosomal recessive disorder characterized by congenital sensorineural hearing loss, progressive retinitis pigmentosa (RP), and variable vestibular dysfunction. It is the most common cause of hereditary deaf-blindness, with three clinical subtypes (1–3) differing in hearing loss severity, onset of RP, and balance impairment [1][6][10]. Diagnosis relies on genetic testing, audiologic evaluation, and ophthalmologic assessment [16].
Burden
Progressive sensory deficits lead to communication barriers, mobility challenges, and increased fall risk [16][19].
Severe psychosocial impact due to dual sensory loss; ~30% of patients report depression/anxiety [19].
Requires lifelong multidisciplinary care, with genetic counseling critical for family planning [5][20].
Early intervention (e.g., cochlear implants <2 years) and dual-sensory clinics optimize outcomes [16][20].
Therapies
Hearing: Cochlear implants (type 1), hearing aids (types 2/3), and auditory-verbal therapy [3][8][16].
Vision: Vitamin A supplementation (excluding type 1), low-vision aids, and gene therapy trials targeting USH2A mutations [5][10][13].
Emerging: Exon-skipping, nonsense suppression drugs (ataluren), and dual AAV vectors for gene replacement [5][13][18].
Categories: rare developmental anomalies during embryogenesis, rare genetic diseases, rare ophthalmic disorders, rare otorhinolaryngological diseases
Research Papers
422 drug discovery papers about Usher syndrome, with 2 first-in-class and 7 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
422 drug discovery papers about Usher syndrome, with 2 first-in-class and 7 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-08-03 | CLRN1 Variants in Müller Cells Cause Mitochondrial Dysfunction in USH3A Retinal Organoids.
Usher syndrome 3A (USH3A), caused by mutations in the CLRN1 gene, leads to retinitis pigmentosa and sensorineural hearing loss. While CLRN1's role in inner ear pathology is established, its contribution to retinal degeneration remains poorly understood. Retinal organoids derived from a USH3A patient were analyzed using single-cell RNA sequencing and multi-electrode array recording. CLRN1 expression was mapped in human fetal retina and organoids. We assessed the structural, transcriptional, and functional impact of CLRN1 variants on Müller cells and photoreceptors, and evaluated idebenone as a potential targeted therapy. CLRN1 was specifically expressed in Müller cells. CLRN1 variants induced severe retinal degeneration, characterized by outer nuclear layer thinning, impaired photoreceptor gene expression, activated apoptosis, and diminished electrophysiological function. Mechanistically, these variants caused mitochondrial dysfunction in Müller cells, which triggered secondary mitochondrial impairment, oxidative stress, and apoptosis in photoreceptors. Idebenone treatment partially rescued these deficits. CLRN1-related mitochondrial impairment in Müller cells contributes to the pathogenesis of retinitis pigmentosa in USH3A. These findings identify Müller cell mitochondrial dysfunction as a key disease mechanism and highlight potential therapeutic targets.
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.
2026-07-20 | Cholesterol Conjugation Strategies to Enhance In Vivo Antisense Oligonucleotide-Mediated Exon Skipping in the Mouse Retina.
Antisense oligonucleotide (AON)-mediated exon skipping is a potential therapeutic approach to certain inherited retinal diseases, including Usher's Syndrome Type 2 A. Heteroduplex AONs (HAONs) have been reported to enhance RNA-modulating activity in vivo; this study evaluated whether the HAON strategy improves Ush2a exon skipping activity in the mouse retina. AONs of different chemical makeup targeting Ush2a exon 12 were formulated as HAONs with and without lipid conjugation. Activity was evaluated in 2D and 3D cell models and in the mouse eye following intravitreal administration. Lipid conjugation was required to increase activity in the mouse retina. However, exon-skipping effects observed for cholesterol (Chol)-conjugated HAONs in vivo were not reflected in cell models. A single dose of HAONs bearing a Chol on either strand or the Chol-AON conjugate produced up to a 4.6-fold increase in Ush2a exon 12 skipping in mouse retina over AON alone, with effects lasting at least 28 days without major tolerability findings. Chol conjugation-either to a HAON construct or directly to the AON-can substantially enhance the potency of retina-targeted exon-skipping AON therapies in vivo.
2026-07-10 | Single-cell analysis reveals impaired Müller glia-mediated intercellular communication and photoreceptor pathology in USH1C retinal organoids.
Usher syndrome type 1, caused by pathogenic variants in the USH1C gene, leads to congenital deafness and progressive retinal degeneration resulting in vision loss. While auditory deficits can be compensated by cochlea implants and hearing aids, no treatment exists to prevent retinal degeneration. Here, we generated retinal organoids from induced pluripotent stem cells of two USH1C patients to elucidate the cellular and molecular mechanisms driving ocular pathogenesis. Single-cell RNA sequencing of healthy and USH1C retinal organoids identified differential expression of genes related to phototransduction in photoreceptors, as well as alterations in cell adhesion and canonical Wnt signaling in Müller glia cells. Analysis of intercellular communication revealed an overall reduced signaling efficiency, particularly affecting Müller glia-mediated retinal adhesion processes. Morphological characterization of organoids confirmed transcriptome changes by showing degeneration of the outer limiting membrane and loss of adherens junction architecture. Moreover, photoreceptors revealed increased levels of apoptosis, as well as morphological and functional changes related to phototransduction. Our results demonstrate that disruption of Müller glia signaling contributes to an overall loss of retinal integrity, providing novel insights into USH1C pathogenesis and offering targets for therapeutic interventions.
2026-07-03 | Gene Supplementation of MYO7A or activation of Myo7b for treatment of Usher syndrome 1B
Abstract Mutations in MYO7A result in the most severe subtype of Usher syndrome, the leading genetic cause of deafblindness. The large size of MYO7A requires dual adeno-associated virus (AAV) vectors for gene transfer or alternative methods to treat retinal defects. Here, we evaluated two treatment approaches: i) Supplementation of the human MYO7A gene via dual mRNA trans-splicing AAVs, and ii) CRISPR/Cas-mediated activation of the related murine Myo7b gene. Upon MYO7A supplementation, the transgenic MYO7A transcript and protein were expressed and correctly localized in retinal pigment epithelial (RPE) and photoreceptors of mice, pigs, and human retinal organoids. In RPE-and photoreceptor-specific Myo7a knockout mice, we could restore MYO7A expression and localization of melanosomes in RPE cells to wild-type levels. Myo7b activation led to partial restoration of melanosome localization, and the localization of MYO7B protein was largely comparable to MYO7A. These findings indicate that both approaches are in principle suitable for the therapy of Usher syndrome.
2026-08-03 | CLRN1 Variants in Müller Cells Cause Mitochondrial Dysfunction in USH3A Retinal Organoids.
Usher syndrome 3A (USH3A), caused by mutations in the CLRN1 gene, leads to retinitis pigmentosa and sensorineural hearing loss. While CLRN1's role in inner ear pathology is established, its contribution to retinal degeneration remains poorly understood. Retinal organoids derived from a USH3A patient were analyzed using single-cell RNA sequencing and multi-electrode array recording. CLRN1 expression was mapped in human fetal retina and organoids. We assessed the structural, transcriptional, and functional impact of CLRN1 variants on Müller cells and photoreceptors, and evaluated idebenone as a potential targeted therapy. CLRN1 was specifically expressed in Müller cells. CLRN1 variants induced severe retinal degeneration, characterized by outer nuclear layer thinning, impaired photoreceptor gene expression, activated apoptosis, and diminished electrophysiological function. Mechanistically, these variants caused mitochondrial dysfunction in Müller cells, which triggered secondary mitochondrial impairment, oxidative stress, and apoptosis in photoreceptors. Idebenone treatment partially rescued these deficits. CLRN1-related mitochondrial impairment in Müller cells contributes to the pathogenesis of retinitis pigmentosa in USH3A. These findings identify Müller cell mitochondrial dysfunction as a key disease mechanism and highlight potential therapeutic targets.
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.
2026-07-20 | Cholesterol Conjugation Strategies to Enhance In Vivo Antisense Oligonucleotide-Mediated Exon Skipping in the Mouse Retina.
Antisense oligonucleotide (AON)-mediated exon skipping is a potential therapeutic approach to certain inherited retinal diseases, including Usher's Syndrome Type 2 A. Heteroduplex AONs (HAONs) have been reported to enhance RNA-modulating activity in vivo; this study evaluated whether the HAON strategy improves Ush2a exon skipping activity in the mouse retina. AONs of different chemical makeup targeting Ush2a exon 12 were formulated as HAONs with and without lipid conjugation. Activity was evaluated in 2D and 3D cell models and in the mouse eye following intravitreal administration. Lipid conjugation was required to increase activity in the mouse retina. However, exon-skipping effects observed for cholesterol (Chol)-conjugated HAONs in vivo were not reflected in cell models. A single dose of HAONs bearing a Chol on either strand or the Chol-AON conjugate produced up to a 4.6-fold increase in Ush2a exon 12 skipping in mouse retina over AON alone, with effects lasting at least 28 days without major tolerability findings. Chol conjugation-either to a HAON construct or directly to the AON-can substantially enhance the potency of retina-targeted exon-skipping AON therapies in vivo.
2026-07-10 | Single-cell analysis reveals impaired Müller glia-mediated intercellular communication and photoreceptor pathology in USH1C retinal organoids.
Usher syndrome type 1, caused by pathogenic variants in the USH1C gene, leads to congenital deafness and progressive retinal degeneration resulting in vision loss. While auditory deficits can be compensated by cochlea implants and hearing aids, no treatment exists to prevent retinal degeneration. Here, we generated retinal organoids from induced pluripotent stem cells of two USH1C patients to elucidate the cellular and molecular mechanisms driving ocular pathogenesis. Single-cell RNA sequencing of healthy and USH1C retinal organoids identified differential expression of genes related to phototransduction in photoreceptors, as well as alterations in cell adhesion and canonical Wnt signaling in Müller glia cells. Analysis of intercellular communication revealed an overall reduced signaling efficiency, particularly affecting Müller glia-mediated retinal adhesion processes. Morphological characterization of organoids confirmed transcriptome changes by showing degeneration of the outer limiting membrane and loss of adherens junction architecture. Moreover, photoreceptors revealed increased levels of apoptosis, as well as morphological and functional changes related to phototransduction. Our results demonstrate that disruption of Müller glia signaling contributes to an overall loss of retinal integrity, providing novel insights into USH1C pathogenesis and offering targets for therapeutic interventions.
2026-07-03 | Gene Supplementation of MYO7A or activation of Myo7b for treatment of Usher syndrome 1B
Abstract Mutations in MYO7A result in the most severe subtype of Usher syndrome, the leading genetic cause of deafblindness. The large size of MYO7A requires dual adeno-associated virus (AAV) vectors for gene transfer or alternative methods to treat retinal defects. Here, we evaluated two treatment approaches: i) Supplementation of the human MYO7A gene via dual mRNA trans-splicing AAVs, and ii) CRISPR/Cas-mediated activation of the related murine Myo7b gene. Upon MYO7A supplementation, the transgenic MYO7A transcript and protein were expressed and correctly localized in retinal pigment epithelial (RPE) and photoreceptors of mice, pigs, and human retinal organoids. In RPE-and photoreceptor-specific Myo7a knockout mice, we could restore MYO7A expression and localization of melanosomes in RPE cells to wild-type levels. Myo7b activation led to partial restoration of melanosome localization, and the localization of MYO7B protein was largely comparable to MYO7A. These findings indicate that both approaches are in principle suitable for the therapy of Usher syndrome.
Access all drug discovery papers and probability of success in trials forecasts:
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Drug Discovery Landscape
4 orphan drug designations for Usher syndrome.
4 orphan drug designations for Usher syndrome.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
dual adeno-associated viral vector serotype 8 encoding for human myosin VIIA (MYO7A) | gene therapies | FDA | 2024-10-29 | — | AAVantgarde Bio SRL |
(E)-2-((4-((4-Benzyl(ethyl)amino)phenyl)diazinyl)phenyl)amino-N,N,N-triethyl-2-oxoethan-1-aminium chloride | small molecules | EMA | 2024-08-21 | — | Kiora Pharmaceuticals GmbH |
1-(4-Chloro-3,5-diphenyl-pyrazolo[3,4-c]pyridazin-1-yl)-2-methyl-propan-2-ol | small molecules | FDA | 2019-11-26 | — | Usher III Initiative, Inc. |
Mixture of two adeno-associated viral vectors of serotype 8 containing the 5'-half sequence of human MYO7A gene and the 3'-half sequence of human MYO7A gene | gene therapies | EMA | 2014-07-04 | — | Aavantgarde Bio S.r.l. |
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