RARE DISEASE
Usher syndrome type 1
Usher syndrome type 1
Usher syndrome type 1
Synonyms: USH1
Synonyms: USH1
Synonyms: USH1
Drug discovery
2
drugs
With orphan designations
Overview
Usher Syndrome Type 1 (USH1) is an autosomal recessive disorder characterized by congenital profound sensorineural hearing loss, prepubertal-onset retinitis pigmentosa (RP), and vestibular areflexia. Balance issues delay motor milestones (e.g., walking after 18 months), while RP progresses from night blindness to legal blindness by mid-adulthood. Early cochlear implantation improves auditory outcomes, but no treatments prevent RP progression [1][3][6][10].
Categories: rare developmental anomalies during embryogenesis, rare genetic diseases, rare ophthalmic disorders, rare otorhinolaryngological diseases
Research Papers
141 drug discovery papers about Usher syndrome type 1, with 3 first-in-class and 2 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
141 drug discovery papers about Usher syndrome type 1, with 3 first-in-class and 2 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-04-28 | Expanding the options for therapeutic exon skipping as a future treatment for USH2A -associated disease by 3D structural modeling of newly formed hybrid domains
ABSTRACT Usher syndrome, the leading cause of hereditary deaf-blindness affecting approximately 1 in 15,000 individuals worldwide, is currently still untreatable. Antisense oligonucleotide-based exon skipping has shown significant therapeutic promise for USH2A -associated retinal dysfunction. Selection of (combinations of) exons suitable for therapeutic exon skipping within the fibronectin type 3 (FN3) domain-encoding region of USH2A currently requires that skipped exons exactly align with complete protein domains. However, only few exon combinations meet this criterion, which significantly restricts the therapeutic potential of this strategy. Our study addresses this limitation by incorporating AlphaFold2 structural modelling into the exon skipping target selection pipeline. Following this adjusted framework, we can predict exon skipping combinations that allow remaining domain fragments to form structurally viable hybrid domains. As a proof-of-concept, we examined and confirmed the functionality of usherinΔexon54-58 that contains a hybrid FN3 domain, using zebrafish as a model. This highligts the potential of the newly developed paradigm for identifying exon skipping targets with potential therapeutic relevance. Our results emphasize the value of structural modeling in identifying new therapeutic exon skipping targets, aiming to improve precision, efficiency, applicability, and cost-effectiveness in the development of genetic therapies for hereditary diseases such as Usher syndrome.
2026-02-12 | Myosin 7a is required for maintaining the transducing stereocilia and for force transmission to the MET channel during cochlear hair cell development
Abstract Shaker‐1 mice carry a spontaneous missense mutation in Myo7a ( Myo7a Sh1 ) that interferes with the motor function of MYO7A. Mutation in the orthologous gene in humans causes syndromic (Usher 1B) or non‐syndromic forms of deafness. In hair cells, MYO7A is expressed throughout the stereocilia, where it has been implicated in tip‐link tensioning required for gating the mechanoelectrical transducer (MET) channel and setting its resting open probability ( P o ). The Myo7a Sh1 mutation progressively dysregulated the height of shorter stereocilia rows from the end of the first postnatal week onwards, associated with reduced MET current amplitude and hearing loss. Noise exposure exacerbated stereocilia dysfunction in Myo7a Sh1/Sh1 mice. Following the onset of maturation, hair cells from Myo7a Sh1/Sh1 mice showed normal resting P o and calcium sensitivity of the MET channel. In immature Myo7a Sh1/Sh1 hair cells, the resting P o was very small or absent in comparison to control cells, but it was restored by changing the membrane lipid bilayer fluidity or thickness by depleting cholesterol or PIP 2 . Bundle stiffness in immature IHCs was not affected by the absence of functional MYO7A but decreased after their onset of maturation in both genotypes. Expression of a subset of genes was affected similarly in immature Myo7a Sh1/Sh1 mice and in adult Myo7a conditional knockout mice, indicating a common response pathway in Myo7a ‐deficient mice. This study reveals that MET channel gating might differ depending on hair cell developmental stage, and MYO7A is likely to influence, albeit indirectly, force transmission via the lipid bilayer to the MET channel and maintenance of the shorter rows of transducing stereocilia. image Key points Shaker‐1 mice carry a spontaneous missense mutation in the shaker‐1 gene ( Myo7a Sh1 ) that interferes with the motor function of MYO7A, a protein expressed in hair‐cell stereocilia. The absence of functional MYO7A ( Myo7a Sh1/Sh1 mice) caused a progressive dysregulation in the height of the shortest two rows of stereocilia and the consequent loss of mechanoelectrical transduction (MET) current. Although immature hair cells from Myo7a Sh1/Sh1 mice exhibited a markedly reduced resting open probability of their MET channels, this was restored upon maturation or following depletion of cholesterol or PIP 2 from the lipid bilayer. Hair‐bundle stiffness was affected in immature inner hair cells from Myo7a Sh1/Sh1 mice, suggesting that MYO7A is not required for establishing the resting tension of the tip links gating the MET channels. We conclude that MYO7A is crucial for the structural integrity of the MET complex and transport of key proteins required to transfer forces efficiently from the lipid bilayer to the MET channel.
2025-11-26 | Clinical Findings and Molecular Genetics of USH1C-Associated Usher Syndrome.
Expanding insight into the phenotypic spectrum, social burden of dual sensory impairment, and progression of USH1C-associated retinopathy is essential to inform prognosis and guide emerging therapies. To characterize some genetic variants, clinical features, natural history, and social outcomes of USH1C-associated retinopathy in a patient cohort. This was a retrospective case series including patients with molecularly confirmed UCH1C-associated retinopathy evaluated at a tertiary referral center from January 1989 to February 2024. Molecularly confirmed pathogenic variants in USH1C. Main outcomes included best-corrected visual acuity (BCVA) measured with the Snellen chart, retinal imaging features, genetic variants, and patient-reported social outcomes. Depression was documented by general practitioners using the Patient Health Questionnaire 9. Unemployment was self-reported at last follow-up. Retinitis pigmentosa diagnosis (RP) was diagnosed based on characteristic retinal findings and visual field loss. A total of 28 patients (mean [SD] age, 27.0 [12.2] years; range, 7-58 years; 15 female [53.6%]) were included in this analysis. Two novel pathogenic USH1C variants were identified; 18 patients were homozygous. Presenting symptoms included nyctalopia (24 of 26 patients [92.3%]) and peripheral vision difficulties (23 of 28 patients [82.1%]). Baseline BCVA (Snellen chart) in the better-seeing eye (n = 25) was 0.22 logMAR (20/32). Among 15 patients with follow-up of 5 years or more, baseline BCVA was 0.30 logMAR (20/40), declining to 0.59 logMAR (20/80). In Early Treatment Diabetic Retinopathy Study (ETDRS) equivalents (n = 15), decline averaged 0.53 letters per year (median, 0; range, 0-2). Four of 24 patients (16.7%) met World Health Organization criteria for severe sight impairment (20/200 or worse in the better-seeing eye). Depression was reported by 5 of 13 patients (38.5%) and unemployment by 7 of 23 patients (30.4%). Optical coherence tomography revealed cystoid macular edema in 5 of 21 patients at baseline, persisting in 2 patients at follow-up. Mean (SD) central subfield thickness was 260.6 (53.6) µm at baseline (n = 18) and 259.4 (44.5) µm at follow-up (n = 15). Patients with missense variants c.308G>A (p.Arg103His) and c.440A>G (p.His147Arg) showed retinitis pigmentosa sparing the superior retina. Results of this case series study suggest that USH1C-associated retinopathy was characterized by slow decline of visual acuity and modest ellipsoid zone loss over decades. Depression and unemployment were also observed, with implications for prognosis and counseling. Early onset and slow progression highlight its potential as a target for emerging therapies.
2025-10-08 | Identification of a variant in the USH1G gene in a family with Usher syndrome.
Usher syndrome is characterized by congenital sensorineural hearing loss, retinitis pigmentosa, and vestibular dysfunction. It is the most common cause of deafblindness worldwide. It is classified into three clinical types and twelve genetic subtypes. We report a case of a family affected by Usher syndrome due to a variant in the USH1G gene, coding for the SANS protein. The ocular and auditory tests were performed for clinical confirmation of the diagnosis. The molecular study consisted of a next-generation sequencing panel containing 14 genes associated with Usher syndrome: MYO7A, USHC1, CDH23, PCDH15, USHG1, CIB2, USH2A, ADGRV1, WHRN, CLRN1, HARS, PDZD7, CEP250, C2orf71. We present the case of a 13-year-old girl from a consanguineous Colombian family diagnosed with Usher syndrome type 1G. Clinical evaluations confirmed auditory, vestibular, and ocular alterations. Molecular analysis identified the homozygous p.Glu171Ter variant in the USH1G gene. We highlight the importance of an early diagnosis of Usher syndrome. Although the variant frequency in the USH1G gene is low, it should not be underestimated; the exact etiology must be identified in these families. We recommend establishing a panel with Colombianspecific variants to perform more accurate Usher syndrome diagnoses, and in the future, to guide the development of gene therapies.
2025-09-28 | Adeno-associated virus-based rescue of Myo7a expression restores hair-cell function and improves hearing thresholds in a USH1B mouse strain.
Mutations in MYO7A, the gene encoding the unconventional myosin 7a, cause hereditary deafness in mice and humans. In the cochlea, MYO7A is present in the sensory hair cells from embryonic stages of development, and plays a critical role in the development and maintenance of the mechanosensitive hair bundles composed of actin-rich stereocilia. Shaker-1 mutant mice (Myo7aSh1/Sh1), the murine model of Usher 1B syndrome, exhibit a progressive loss of the stereocilia, subsequent degeneration of the sensory epithelium and ultimately profound deafness. In addition to the hair bundle defects, we found that the shaker-1 mutation prevented both inner hair cells (IHCs) and outer hair cells (OHCs) from acquiring their fully mature basolateral current profile. Delivering exogenous Myo7a to newborn Myo7aSh1/Sh1 mice using dual-adeno-associated virus 8 (AAV8)-Myo7a or dual-AAV9-PhP.eB-Myo7a, which primarily target IHCs, led to a substantial rescue of their hair bundle structure. The rescued bundles regained their ability to generate mechanoelectrical transducer (MET) currents in response to fluid jet displacement. Although the average MET current was smaller than in control IHCs, the normal resting open probability of the MET channel was fully restored. The IHCs of the treated cochlea also regained a mature basolateral membrane current profile. Functionally, rescue of the IHC structure and function, but not that of OHCs, leads to an average improvement of 20-30 dB in hearing thresholds across most frequencies. These results support dual AAV-induced gene replacement therapy as an effective strategy to recover hair-cell function in Myo7aSh1/Sh1 mice. KEY POINTS: Shaker-1 mutant mice (Myo7aSh1/Sh1), which carry a mutation in the unconventional myosin MYO7A and are the murine model of Usher 1B syndrome, become profoundly deaf at 1 month of age or soon after. In the mammalian cochlea, MYO7A is expressed in the hair cells, including within their actin-rich stereociliary bundles. We show that hair cells of Myo7aSh1/Sh1 mice progressively lose their transducing stereocilia and mechanoelectrical transduction, and fail to acquire their fully mature basolateral current profile. Delivering exogenous Myo7a to newborn Myo7aSh1/Sh1 mice using dual-adeno-associated virus (AAVs) led to a substantial rescue of the bundle structure and function of inner hair cells, including mechanoelectrical transduction. This functional rescue led to a 20-30 dB improvement in hearing thresholds across most frequencies. These results support dual AAV-induced gene replacement therapy as an effective strategy to recover the hair-cell function in Myo7aSh1/Sh1 mice.
2026-04-28 | Expanding the options for therapeutic exon skipping as a future treatment for USH2A -associated disease by 3D structural modeling of newly formed hybrid domains
ABSTRACT Usher syndrome, the leading cause of hereditary deaf-blindness affecting approximately 1 in 15,000 individuals worldwide, is currently still untreatable. Antisense oligonucleotide-based exon skipping has shown significant therapeutic promise for USH2A -associated retinal dysfunction. Selection of (combinations of) exons suitable for therapeutic exon skipping within the fibronectin type 3 (FN3) domain-encoding region of USH2A currently requires that skipped exons exactly align with complete protein domains. However, only few exon combinations meet this criterion, which significantly restricts the therapeutic potential of this strategy. Our study addresses this limitation by incorporating AlphaFold2 structural modelling into the exon skipping target selection pipeline. Following this adjusted framework, we can predict exon skipping combinations that allow remaining domain fragments to form structurally viable hybrid domains. As a proof-of-concept, we examined and confirmed the functionality of usherinΔexon54-58 that contains a hybrid FN3 domain, using zebrafish as a model. This highligts the potential of the newly developed paradigm for identifying exon skipping targets with potential therapeutic relevance. Our results emphasize the value of structural modeling in identifying new therapeutic exon skipping targets, aiming to improve precision, efficiency, applicability, and cost-effectiveness in the development of genetic therapies for hereditary diseases such as Usher syndrome.
2026-02-12 | Myosin 7a is required for maintaining the transducing stereocilia and for force transmission to the MET channel during cochlear hair cell development
Abstract Shaker‐1 mice carry a spontaneous missense mutation in Myo7a ( Myo7a Sh1 ) that interferes with the motor function of MYO7A. Mutation in the orthologous gene in humans causes syndromic (Usher 1B) or non‐syndromic forms of deafness. In hair cells, MYO7A is expressed throughout the stereocilia, where it has been implicated in tip‐link tensioning required for gating the mechanoelectrical transducer (MET) channel and setting its resting open probability ( P o ). The Myo7a Sh1 mutation progressively dysregulated the height of shorter stereocilia rows from the end of the first postnatal week onwards, associated with reduced MET current amplitude and hearing loss. Noise exposure exacerbated stereocilia dysfunction in Myo7a Sh1/Sh1 mice. Following the onset of maturation, hair cells from Myo7a Sh1/Sh1 mice showed normal resting P o and calcium sensitivity of the MET channel. In immature Myo7a Sh1/Sh1 hair cells, the resting P o was very small or absent in comparison to control cells, but it was restored by changing the membrane lipid bilayer fluidity or thickness by depleting cholesterol or PIP 2 . Bundle stiffness in immature IHCs was not affected by the absence of functional MYO7A but decreased after their onset of maturation in both genotypes. Expression of a subset of genes was affected similarly in immature Myo7a Sh1/Sh1 mice and in adult Myo7a conditional knockout mice, indicating a common response pathway in Myo7a ‐deficient mice. This study reveals that MET channel gating might differ depending on hair cell developmental stage, and MYO7A is likely to influence, albeit indirectly, force transmission via the lipid bilayer to the MET channel and maintenance of the shorter rows of transducing stereocilia. image Key points Shaker‐1 mice carry a spontaneous missense mutation in the shaker‐1 gene ( Myo7a Sh1 ) that interferes with the motor function of MYO7A, a protein expressed in hair‐cell stereocilia. The absence of functional MYO7A ( Myo7a Sh1/Sh1 mice) caused a progressive dysregulation in the height of the shortest two rows of stereocilia and the consequent loss of mechanoelectrical transduction (MET) current. Although immature hair cells from Myo7a Sh1/Sh1 mice exhibited a markedly reduced resting open probability of their MET channels, this was restored upon maturation or following depletion of cholesterol or PIP 2 from the lipid bilayer. Hair‐bundle stiffness was affected in immature inner hair cells from Myo7a Sh1/Sh1 mice, suggesting that MYO7A is not required for establishing the resting tension of the tip links gating the MET channels. We conclude that MYO7A is crucial for the structural integrity of the MET complex and transport of key proteins required to transfer forces efficiently from the lipid bilayer to the MET channel.
2025-11-26 | Clinical Findings and Molecular Genetics of USH1C-Associated Usher Syndrome.
Expanding insight into the phenotypic spectrum, social burden of dual sensory impairment, and progression of USH1C-associated retinopathy is essential to inform prognosis and guide emerging therapies. To characterize some genetic variants, clinical features, natural history, and social outcomes of USH1C-associated retinopathy in a patient cohort. This was a retrospective case series including patients with molecularly confirmed UCH1C-associated retinopathy evaluated at a tertiary referral center from January 1989 to February 2024. Molecularly confirmed pathogenic variants in USH1C. Main outcomes included best-corrected visual acuity (BCVA) measured with the Snellen chart, retinal imaging features, genetic variants, and patient-reported social outcomes. Depression was documented by general practitioners using the Patient Health Questionnaire 9. Unemployment was self-reported at last follow-up. Retinitis pigmentosa diagnosis (RP) was diagnosed based on characteristic retinal findings and visual field loss. A total of 28 patients (mean [SD] age, 27.0 [12.2] years; range, 7-58 years; 15 female [53.6%]) were included in this analysis. Two novel pathogenic USH1C variants were identified; 18 patients were homozygous. Presenting symptoms included nyctalopia (24 of 26 patients [92.3%]) and peripheral vision difficulties (23 of 28 patients [82.1%]). Baseline BCVA (Snellen chart) in the better-seeing eye (n = 25) was 0.22 logMAR (20/32). Among 15 patients with follow-up of 5 years or more, baseline BCVA was 0.30 logMAR (20/40), declining to 0.59 logMAR (20/80). In Early Treatment Diabetic Retinopathy Study (ETDRS) equivalents (n = 15), decline averaged 0.53 letters per year (median, 0; range, 0-2). Four of 24 patients (16.7%) met World Health Organization criteria for severe sight impairment (20/200 or worse in the better-seeing eye). Depression was reported by 5 of 13 patients (38.5%) and unemployment by 7 of 23 patients (30.4%). Optical coherence tomography revealed cystoid macular edema in 5 of 21 patients at baseline, persisting in 2 patients at follow-up. Mean (SD) central subfield thickness was 260.6 (53.6) µm at baseline (n = 18) and 259.4 (44.5) µm at follow-up (n = 15). Patients with missense variants c.308G>A (p.Arg103His) and c.440A>G (p.His147Arg) showed retinitis pigmentosa sparing the superior retina. Results of this case series study suggest that USH1C-associated retinopathy was characterized by slow decline of visual acuity and modest ellipsoid zone loss over decades. Depression and unemployment were also observed, with implications for prognosis and counseling. Early onset and slow progression highlight its potential as a target for emerging therapies.
2025-10-08 | Identification of a variant in the USH1G gene in a family with Usher syndrome.
Usher syndrome is characterized by congenital sensorineural hearing loss, retinitis pigmentosa, and vestibular dysfunction. It is the most common cause of deafblindness worldwide. It is classified into three clinical types and twelve genetic subtypes. We report a case of a family affected by Usher syndrome due to a variant in the USH1G gene, coding for the SANS protein. The ocular and auditory tests were performed for clinical confirmation of the diagnosis. The molecular study consisted of a next-generation sequencing panel containing 14 genes associated with Usher syndrome: MYO7A, USHC1, CDH23, PCDH15, USHG1, CIB2, USH2A, ADGRV1, WHRN, CLRN1, HARS, PDZD7, CEP250, C2orf71. We present the case of a 13-year-old girl from a consanguineous Colombian family diagnosed with Usher syndrome type 1G. Clinical evaluations confirmed auditory, vestibular, and ocular alterations. Molecular analysis identified the homozygous p.Glu171Ter variant in the USH1G gene. We highlight the importance of an early diagnosis of Usher syndrome. Although the variant frequency in the USH1G gene is low, it should not be underestimated; the exact etiology must be identified in these families. We recommend establishing a panel with Colombianspecific variants to perform more accurate Usher syndrome diagnoses, and in the future, to guide the development of gene therapies.
2025-09-28 | Adeno-associated virus-based rescue of Myo7a expression restores hair-cell function and improves hearing thresholds in a USH1B mouse strain.
Mutations in MYO7A, the gene encoding the unconventional myosin 7a, cause hereditary deafness in mice and humans. In the cochlea, MYO7A is present in the sensory hair cells from embryonic stages of development, and plays a critical role in the development and maintenance of the mechanosensitive hair bundles composed of actin-rich stereocilia. Shaker-1 mutant mice (Myo7aSh1/Sh1), the murine model of Usher 1B syndrome, exhibit a progressive loss of the stereocilia, subsequent degeneration of the sensory epithelium and ultimately profound deafness. In addition to the hair bundle defects, we found that the shaker-1 mutation prevented both inner hair cells (IHCs) and outer hair cells (OHCs) from acquiring their fully mature basolateral current profile. Delivering exogenous Myo7a to newborn Myo7aSh1/Sh1 mice using dual-adeno-associated virus 8 (AAV8)-Myo7a or dual-AAV9-PhP.eB-Myo7a, which primarily target IHCs, led to a substantial rescue of their hair bundle structure. The rescued bundles regained their ability to generate mechanoelectrical transducer (MET) currents in response to fluid jet displacement. Although the average MET current was smaller than in control IHCs, the normal resting open probability of the MET channel was fully restored. The IHCs of the treated cochlea also regained a mature basolateral membrane current profile. Functionally, rescue of the IHC structure and function, but not that of OHCs, leads to an average improvement of 20-30 dB in hearing thresholds across most frequencies. These results support dual AAV-induced gene replacement therapy as an effective strategy to recover hair-cell function in Myo7aSh1/Sh1 mice. KEY POINTS: Shaker-1 mutant mice (Myo7aSh1/Sh1), which carry a mutation in the unconventional myosin MYO7A and are the murine model of Usher 1B syndrome, become profoundly deaf at 1 month of age or soon after. In the mammalian cochlea, MYO7A is expressed in the hair cells, including within their actin-rich stereociliary bundles. We show that hair cells of Myo7aSh1/Sh1 mice progressively lose their transducing stereocilia and mechanoelectrical transduction, and fail to acquire their fully mature basolateral current profile. Delivering exogenous Myo7a to newborn Myo7aSh1/Sh1 mice using dual-adeno-associated virus (AAVs) led to a substantial rescue of the bundle structure and function of inner hair cells, including mechanoelectrical transduction. This functional rescue led to a 20-30 dB improvement in hearing thresholds across most frequencies. These results support dual AAV-induced gene replacement therapy as an effective strategy to recover the hair-cell function in Myo7aSh1/Sh1 mice.
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Drug Discovery Landscape
2 orphan drug designations for Usher syndrome type 1.
2 orphan drug designations for Usher syndrome type 1.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
lentiviral vector containing the human MY07A gene | gene therapies | FDA | 2010-05-17 | — | Sanofi US Services Inc. |
Lentiviral vector containing the human MYO7A gene | gene therapies | EMA | 2010-03-23 | — | Sanofi Winthrop Industrie |
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