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 related to Usher syndrome type 1, with 3 first-in-class and 2 next-in-class early-stage therapies forecasted to outperform the average preclinical success rate. Recent publications:
141 drug discovery papers related to Usher syndrome type 1, with 3 first-in-class and 2 next-in-class early-stage therapies 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.
2026-04-23 | Multicenter Natural History Study and Long-Term Cochlear Implant Outcomes in Usher Syndrome Subtypes
OBJECTIVES: Usher syndrome (USH) is an inherited disorder that causes bilateral sensorineural hearing loss (SNHL), retinitis pigmentosa, and vestibular defects. It represents the most common cause of combined deaf-blindness worldwide. Mutations in the nine known underlying genes are categorized into three types: USH type 1 has the earliest, most severe onset, while the much more common USH type 2 is comparatively mild with delayed onset and moderate symptoms. USH type 3 is very rare and exhibits variable clinical manifestations. The current standard of care for SNHL in USH is comprised of conventional hearing aids and/or cochlear implantation depending on the severity of symptoms. However, existing studies on treatment outcomes generally have rather short follow-up durations from a single institution and rarely distinguish between the individual USH subtypes. DESIGN: This retrospective multicenter cohort study analyzed 655 audiograms of 33 patients (66 ears) with genetically confirmed USH. Patient-specific characteristics and treatments were correlated with pure-tone average thresholds and speech perception performance over a mean (SD) of 7 yrs and 10 mo (9 yrs and 11 mo) overall and 8 yrs and 2 mo (6 yrs and 3 mo) after cochlear implantation. RESULTS: Conventional hearing aids improved thresholds on average (SD) by 20.1 (10.9) dB HL regardless of age, but aided hearing still deteriorated concurrently with the natural progression of SNHL. In patients with severe-to-profound SNHL or complete deafness, cochlear implantation rescued hearing to average thresholds of 37.9 (7.0) dB HL 1 yr post-implantation, 37.3 (10.3) dB HL after 2 years, and 27.5 (7.1) dB HL after 15 to 20 yrs. Every single patient who received an implant benefited from it, irrespective of the age at implantation or the causative USH mutation. CONCLUSIONS: With new gene therapies for USH in development, the findings reported here can serve as a benchmark for the comparison of novel treatments with the current clinical standard of care around the world. Larger-scale studies with more consistent monitoring of hearing and speech perception ability, as well as more extensive genetic testing, could further elucidate the benefits of current treatments for different (sub-)types of USH.
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.
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.
2026-04-23 | Multicenter Natural History Study and Long-Term Cochlear Implant Outcomes in Usher Syndrome Subtypes
OBJECTIVES: Usher syndrome (USH) is an inherited disorder that causes bilateral sensorineural hearing loss (SNHL), retinitis pigmentosa, and vestibular defects. It represents the most common cause of combined deaf-blindness worldwide. Mutations in the nine known underlying genes are categorized into three types: USH type 1 has the earliest, most severe onset, while the much more common USH type 2 is comparatively mild with delayed onset and moderate symptoms. USH type 3 is very rare and exhibits variable clinical manifestations. The current standard of care for SNHL in USH is comprised of conventional hearing aids and/or cochlear implantation depending on the severity of symptoms. However, existing studies on treatment outcomes generally have rather short follow-up durations from a single institution and rarely distinguish between the individual USH subtypes. DESIGN: This retrospective multicenter cohort study analyzed 655 audiograms of 33 patients (66 ears) with genetically confirmed USH. Patient-specific characteristics and treatments were correlated with pure-tone average thresholds and speech perception performance over a mean (SD) of 7 yrs and 10 mo (9 yrs and 11 mo) overall and 8 yrs and 2 mo (6 yrs and 3 mo) after cochlear implantation. RESULTS: Conventional hearing aids improved thresholds on average (SD) by 20.1 (10.9) dB HL regardless of age, but aided hearing still deteriorated concurrently with the natural progression of SNHL. In patients with severe-to-profound SNHL or complete deafness, cochlear implantation rescued hearing to average thresholds of 37.9 (7.0) dB HL 1 yr post-implantation, 37.3 (10.3) dB HL after 2 years, and 27.5 (7.1) dB HL after 15 to 20 yrs. Every single patient who received an implant benefited from it, irrespective of the age at implantation or the causative USH mutation. CONCLUSIONS: With new gene therapies for USH in development, the findings reported here can serve as a benchmark for the comparison of novel treatments with the current clinical standard of care around the world. Larger-scale studies with more consistent monitoring of hearing and speech perception ability, as well as more extensive genetic testing, could further elucidate the benefits of current treatments for different (sub-)types of USH.
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.
Access all drug discovery articles and probability of success in trials forecasts:
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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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