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:
categories:
Small molecules
proteins
2026-05-29 | REGULATION OF FORCE TRANSMISSION IN MECHANO-ELECTRICAL TRANSDUCTION CHANNELS OF MAMMALIAN AUDITORY HAIR CELLS
Sound perception relies on specialized actin-based structures called stereocilia, located on the apical surface of auditory hair cells (HCs). Stereocilia are arranged in three rows of increasing height and interconnected with extracellular tip links. Sound-induced vibrations modulate tension on these tip-links, leading to the opening or closing of mechanically gated ion channels that allow cation influx inside the cell, which ultimately generates a neural signal. In recent years, it has been established that the mechano-electrical transduction (MET) channel is constituted by an elaborate complex of multiple proteins associated with the channel itself and with the lower end of the tip-link. However, the molecular and biophysical mechanisms by which external forces are transmitted from the tip-link to the channel are yet unknown, along with the exact role of each protein of MET complex and the plasma membrane in this process. This study represents the first systematic investigation of the MET channel activation in wild type HCs and HCs with deafness-associated variant of Calcium and Integrin-Binding protein 2 (CIB2). CIB2 is essential for hearing and MET in mammalian auditory HCs. CIB2 interacts with TMC1/2, the pore-forming subunits of the MET channel, and is needed for their localization to stereocilia. However, the molecular mechanism by which CIB2 regulates channel activity remains unclear. We generated a mouse model carrying the Cib2 p.R186W mutation that results in deafness but partially preserves MET currents in young postnatal auditory HCs. We found that the p.R186W variant increases resting open probability (Popen) of MET channels and steepens current-displacement relationships, while abolishing fast adaptation and slowing MET channel activation. This phenotype was not observed in Tmc1Δ/Δ OHCs, indicating that it is not due to altered pore identity. Instead, the slowed MET current kinetics and elevated Popen were consistent with loss of phosphatidylinositol 4,5-bisphosphate (PIP2) from stereocilia. The p.R186W mutation also disrupted localization of the membrane-associated protein BAIAP2L2, and electron-dense structures presumably linked to MET complexes. Pharmacological depletion of PIP2 and BAIAP2L2 in wild-type OHCs reproduced the p.R186W MET current phenotype but did not further affect activation and adaptation in Cib2R186W/R186W OHCs. We conclude that CIB2 is required for proper force transmission to MET channels by coordinating BAIAP2L2 and PIP2 localization at the mechanotransduction site. This study addresses three key questions in the auditory field. First, developing an ultra-fast microfabricated actuator for stereocilia bundle deflection allowed, for the first time, to study systematically the molecular mechanisms underlying MET channel activation in the mammalian auditory hair cells. Second, we found that deafness-associated BAIAP2L2 modulates force sensitivity of the MET channels, most likely through its interactions with the plasma membrane. Finally, this work elucidates the molecular consequences of CIB2 mutations underlying Usher syndrome type 1J and non-syndromic deadness DFNB48, which may contribute to the development of future therapeutic treatments of these devasting diseases.
2026-03-11 | Usherin in the pineal gland: altered sleep in zebrafish models of Usher syndrome type 2a
ABSTRACT Usher syndrome type 2A (USH2a), the most common form of hereditary deaf-blindness, is frequently accompanied by fatigue and poor sleep quality. As these sleep problems occur independently of visual decline, it is hypothesized that the USH2A -encoded protein usherin regulates sleep and circadian rhythmicity via an extra-retinal mechanism. Ush2a knockout zebrafish models were utilized to investigate this hypothesis. Immunohistochemical analysis demonstrated usherin localisation in pineal gland photoreceptor cells in wild-type larvae, alongside the USH2 complex proteins Adgrv1 and Whrna. Cross-species transcriptomic and proteomic analyses confirmed USH2A expression in all mammalian pineal gland tissues studied. Circadian clock gene expression was measured over 24 h and showed preserved oscillatory patterns in wild-type and mutant zebrafish. Ex vivo superfusion of pineal glands revealed sustained circadian melatonin release with comparable phase and period to controls, although potential differences in absolute melatonin levels could not be excluded. Despite intact clock gene expression and melatonin release in ush2a mutants, behavioural classification over 24-h recordings revealed altered sleep-wake behaviour: ush2a mutants displayed elevated daytime sleep and significantly prolonged and more variable sleep latency. The dissociation between intact molecular rhythms and abnormal sleep behaviour likely implicates that usherin plays a role in sleep-wake regulation independent of the circadian pacemaker and melatonin synthesis. These findings suggest a novel role of usherin in the pineal gland and establish a mechanistic link between usherin dysfunction and sleep disturbances, providing a biological basis for the fatigue and sleep problems reported in USH2a patients.
2026-01-23 | Compensatory Interplay Between Clarin-1 and Clarin-2 Deafness-Associated Proteins Governs Phenotypic Variability in Hearing.
Usher syndrome type III (USH3) is a genetic disorder characterized by progressive, post-lingual hearing loss, variable vestibular dysfunction, and onset of retinitis pigmentosa. USH3 is caused by mutations in CLRN1, which encodes clarin-1, a tetraspanin-like protein. Mutations in CLRN2, which encodes the related protein clarin-2, are also implicated in progressive, non-syndromic hearing loss in both humans and mice. USH3 patients show considerable phenotypic variability, even among individuals with the same mutation. This variability may result from environmental factors or interactions with other inner ear genes, such as CLRN2. To investigate the functional interplay of these genes, we generated Clrn1- /-Clrn2-/- double knockout mice. RNA-sequencing and functional/physiological analyses revealed that clarin-1 and clarin-2 jointly regulate mechanoelectrical transduction, ionic homeostasis, and synaptic organization. Their combined loss leads to more severe hearing phenotype compared to Clrn1-/- and Clrn2-/- mice, which reveals a functional compensation between them. CLRN2 variants may exacerbate hearing loss in USH3 patients, supporting inclusion of CLRN2 in genetic screening. By revealing a functional, compensatory interplay between clarin-1 and clarin-2, this study reframes CLRN1-associated deafness as a network-dependent disorder and provides a mechanistic basis for genetic stratification and therapeutic directions in USH3 and related sensorineural hearing loss.
2025-04-16 | Tonotopic Specialization of MYO7A Isoforms in Auditory Hair Cells.
1. Mutations in Myo7a cause Usher syndrome type 1B and non-syndromic deafness, but the precise function of MYO7A in sensory hair cells remains unclear. We identify and characterize a novel isoform, MYO7A-N, expressed in auditory hair cells alongside the canonical MYO7A-C. Isoform-specific knock-in mice reveal that inner hair cells primarily express MYO7A-C, while outer hair cells express both isoforms in opposing tonotopic gradients. Both localize 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.
2025-03-22 | H105A peptide eye drops promote photoreceptor survival in murine and human models of retinal degeneration.
Photoreceptor death leads to inherited blinding retinal diseases, such as retinitis pigmentosa (RP). As disease progression often outpaces therapeutic advances, developing effective treatments is urgent. This study evaluates the efficacy of small peptides derived from pigment epithelium-derived factor (PEDF), which are known to restrict common cell death pathways associated with retinal diseases. We tested chemically synthesized peptides (17-mer and H105A) with affinity for the PEDF receptor, PEDF-R, delivered as eye drops to two RP mouse models: rd10 (phosphodiesterase 6b mutation) and RhoP23H/+ (rhodopsin P23H mutation). Additionally, we engineered AAV-H105A vectors for intravitreal delivery in RhoP23H/+ mice. To assess peptide effects in human tissue, we used retinal organoids exposed to cigarette smoke extract, a model of oxidative stress. Photoreceptor survival, morphology and function were evaluated. Here we show that peptides 17-mer and H105A delivered via eye drops successfully reach the retina, promote photoreceptor survival, and improve retinal function in both RP mouse models. Intravitreal delivery of a AAV-H105A vector delays photoreceptor degeneration in RhoP23H/+ mice up to six months. In human retinal organoids, peptide H105A specifically prevents photoreceptor death induced by oxidative stress, a contributing factor to RP progression. PEDF peptide-based eye drops offer a promising, minimally invasive therapy to prevent photoreceptor degeneration in retinal disorders, with a favorable safety profile.
gene therapies
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.
2026-07-03 | Subretinal injection in the USH1CR31∗ pig model leads to chorioretinal atrophy that limits evaluation of efficacy of an AAV-mediated gene therapy.
Usher syndrome (USH) is the most common form of hereditary deaf-blindness. There is no effective treatment for vision loss to date. Here we aimed to evaluate AAV-mediated ocular gene therapy for USH1C in pigs. USH1CR31∗ and wild type (WT) pigs were bilaterally subretinal injected with 200 μL of 1∗1011 vg/eye Anc80 AAV vectors expressing USH1C_a1 under the control of either a rod-specific human rhodopsin kinase (GRK1) promoter, a ubiquitous promoter (CAG), or vehicle control. Retinal structure and function were assessed by optical coherence tomography and electroretinography (ERG) at baseline and every six months post-injection. Decreased ERG amplitudes and reduction of total retinal thickness were observed in all groups following surgery. At 18 months post-injection, animals were sacrificed and treated and untreated retinal regions were analyzed by qRT-PCR, Western blots, pathohistological examinations, and immunohistochemistry. Both vectors resulted in high levels of USH1C_a1 transcript expression, but only slightly increased harmonin protein expression in USH1CR31∗ pigs. Across all treatment groups, chorioretinal atrophy (CRA) was observed, accompanied by reduced retinal thickness and increased GFAP expression. In conclusion, both vectors achieved efficient retinal transgene delivery in USH1CR31∗ pigs. However, CRA developed in all groups, even in vehicle-injected controls. The extensive retinal damage associated with CRA has likely masked a potentially beneficial therapeutic effect. For future translational development, optimization of dosing, and modifications in surgical technique will be of crucial importance.
2026-07-02 | Müller Glia-Exclusive CLRN1 Expression Drives Non-Cell-Autonomous Photoreceptor Degeneration in Usher Syndrome Type 3A.
Usher syndrome type 3A (USH3A), caused by CLRN1 mutations, leads to progressive deaf-blindness. Although CLRN1 expression has been localized to Müller glia (MG), the pathogenic mechanisms linking glial CLRN1 deficiency to photoreceptor death remain undefined. We utilized a novel large-animal model to elucidate cell-type-specific pathogenesis at single-nucleus resolution. CLRN1-/- rabbits were generated via CRISPR/Cas9. Retinal phenotyping included longitudinal optical coherence tomography (OCT), electroretinography (ERG), and histology for up to 3 years. Single-nucleus RNA sequencing (snRNA-seq) was performed at a pre-symptomatic stage (10 months, n = 3/genotype). Differentially expressed genes (DEGs) were identified using pseudobulk DESeq2 and validated via immunofluorescence. CLRN1-/- rabbits exhibited progressive outer nuclear layer thinning and delayed ERG responses starting after 20 months, mimicking human clinical kinetics. The snRNA-seq revealed that CLRN1 is exclusively expressed in a discrete subset (∼24%) of MG. Mutant MG exhibited transcriptomic downregulation of the adherens junction component CTNNA2, which was validated at the protein level by immunofluorescence staining. Photoreceptors exhibit extensive non-cell-autonomous dysregulation (232 rod and 68 cone DEGs) characterized by loss of the cone synaptic organizer TENM2 and rod-specific splicing dysregulation (CWF19L2). Concurrently, inner retinal neurons mounted a robust proteostatic response via HSP90 family upregulation (HSP90AB1, HSP90AA1, HSP90B1), a defensive signature absent in vulnerable photoreceptors. Our findings suggest an "anchor-shield" mechanism: MG CLRN1 loss compromises the outer limiting membrane (OLM) adhesion complex ("anchor"), and photoreceptors lack the proteostatic response ("shield") seen in resilient inner neurons. Restoring CLRN1 in Müller glia or implementing photoreceptor neuroprotection represents promising therapeutic strategies for USH3A.
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.
2026-01-15 | Reclassification of a novel NR2E3 variant as likely pathogenic: a case report of autosomal recessive RP37 in siblings.
NR2E3 is a nuclear orphan receptor essential for photoreceptor development. Variants in the NR2E3 gene are associated with autosomal recessive retinitis pigmentosa 37 (RP37) and enhanced S-cone syndrome (ESCS). We report a novel NR2E3 variant in a family with RP37, aiming to clarify pathogenicity through clinical and genetic evaluation. The proband, a 26-year-old woman, experienced childhood-onset nyctalopia and progressive vision loss. Fundus exam revealed mid-peripheral pigment clumps and parafoveal depigmentation. Fundus autofluorescence showed widespread hypo-autofluorescent lesions; spectral-domain OCT identified outer nuclear layer thinning and ellipsoid zone loss. Full-field electroretinography confirmed severely diminished scotopic and photopic responses. Her 23-year-old sister had milder pigmentary changes and cystoid macular edema, while their 20-year-old brother's phenotype was less pronounced. All three siblings were homozygous for a novel missense variant in NR2E3 (NM_014249.4:c.352 G > C; p.Val118Leu), located within the DNA-binding domain. Both parents were heterozygous carriers. A previously reported variant affecting the same codon but resulting in a different amino acid change, along with its elevated allele frequency in East Asian populations, suggests a founder effect and supports its pathogenic potential. This report supports reclassifying NR2E3 c.352 G > C (NM_014249.4) as likely pathogenic. A comprehensive genotype-phenotype analysis remains essential for advancing our understanding of NR2E3-associated retinal dystrophies.
small molecules
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.
2026-07-10 | 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.
2026-05-20 | Histidine Supplementation Stabilizes Hearing and Vision and Improves Growth in HARS1-Related Autosomal Recessive Disorder Associated With Usher-Like Symptoms.
Autosomal recessive HARS1-related disorder (originally described as Usher syndrome type 3B) caused by a homozygous Y454S variant in the histidyl-tRNA synthetase gene (HARS1) is characterized by progressive sensorineural hearing and vision loss and respiratory deterioration with risk for sudden death following febrile illnesses. In-vitro studies have previously shown that histidine can rescue a humanized yeast model for pathogenic HARS alleles. Fourteen children homozygous for HARS Y454S were treated with supplemental oral histidine (50 mg/kg BID) and monitored with bloodwork and physical, visual, and audiometry assessments during a 3-year clinical trial, then followed for more than 4 years on histidine in the post-trial period. Patient fibroblasts were assessed for response to histidine. Hearing and vision remained stable, and growth improved significantly. Children remained healthy, with no severe deteriorations despite exposure to bacterial and viral infections, including COVID-19. Gains in growth were maintained in the post-trial period on varying levels of histidine supplementation. Daily oral histidine supplementation in children with autosomal recessive HARS1-related disorder can ameliorate or slow the progression of disease and is safe, inexpensive, and well tolerated. This study adds to the growing list of autosomal recessive ARSopathies (aminoacyl-tRNA synthetase disorders) that are amenable to amino acid supplementation.
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.
2025-05-27 | Advancing Therapeutic Strategies for Nonsense-Related Diseases: From Small Molecules to Nucleic Acid-Based Innovations.
Nonsense mutations in gene coding regions introduce an in-frame premature termination codon (PTC) in the mRNA transcript, resulting in the early termination of translation and the production of a truncated, nonfunctional protein. The absence of protein expression and the consequent loss of essential cellular functions are responsible for the severe phenotypes in the so-called genetic nonsense-related diseases (NRDs), such as cystic fibrosis, hemophilia, Duchenne muscular dystrophy, Fabry disease, Choroideremia, Usher syndrome, Shwachman-Diamond syndrome, and even certain types of cancer. Nonsense mutations pose a significant challenge in the treatment of NRDs, as a specific approach directly addressing this genetic defect is currently unavailable. Developing new therapeutic strategies for nonsense suppression is a crucial goal of precision medicine. This review describes some of the most promising therapeutic approaches and emerging strategies for treating NRDs. It considered both the use of small molecules to interfere with molecular mechanisms related to nonsense mutations, such as translational readthrough-inducing drugs (TRIDs) or inhibitors of the nonsense-mediated decay (NMD) pathway, and also innovative approaches involving nucleic acids, such as gene editing, anticodon engineered-tRNA (ACE-tRNA), or mRNA-based therapy. Future research should focus on refining these approaches and exploring integrated and personalized treatments to enhance therapeutic outcomes and ensure continuous improvement in the quality of care.
oligonucleotides
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.
2026-04-28 | 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.
2025-09-25 | AAV-mediated exon skipping therapy for Usher syndrome, type 2A.
Usher syndrome can cause loss of vision, hearing, and balance. There are four clinical subtypes, USH1-4, which are associated with mutations in genes important for structure, function, and survival of photoreceptor cells in the retina and sensory hair cells in the inner ear. Genetic mutations in the USH2A gene, which encodes usherin protein, are the most common cause of Usher syndrome worldwide, with c.2299delG (p.Glu767Serfs∗21) being the most frequent pathogenic variant. An investigational antisense oligonucleotide (ASO) for USH2A c.2299delG, QR-421a, designed to bypass the mutation, has already shown promise in phase 1/2 clinical trials. While recently developed chemistry provides longer ASO half-lives, repeated injection of ASOs may be required to provide long-term efficacy. To overcome this limitation, we screened novel USH2A exon 13 skippers and 20 AAV capsids with the goal of developing a vectorized ASO exon skipping strategy. Optimized vectors and skippers were evaluated in inner ear and retinal organoids derived from human stem cell lines bearing the USH2A c.2299delG mutation. The data revealed enhanced skipping of the pathogenic exon, offering an alternative strategy for treatment of USH2A patients using a single local injection which may prevent progression of vision and hearing loss.
2025-09-19 | Exon Skipping Therapy Restores Ciliary Function in USH2A-Related Retinal Degeneration.
This study aimed to evaluate the exon-skipping efficacy and safety of an antisense oligonucleotide (AON) targeting USH2A exon 13 across multiple models, including the Rb1 cell line, humanized USH2A-e13 transgenic mice, and patient-derived retinal organoids. Additionally, we investigated the pathogenic mechanisms of USH2A variants and the therapeutic effects of exon skipping on photoreceptor cilia structure and function. Bioinformatic tools were used to design AONs targeting USH2A exon 13, and their exon-skipping efficiency was assessed at both RNA and protein levels in Rb1 cells. A humanized USH2A-e13 transgenic mouse model was generated via gene editing and received intravitreal AON injections. Retinal distribution, exon-skipping efficiency, and toxicity were evaluated through fundus fluorescence imaging, immunofluorescence staining, droplet digital PCR (ddPCR), Western blot (WB), apoptosis assays, and electroretinography (ERG). Patient-derived induced pluripotent stem cells (iPSCs) were differentiated into retinal organoids and analyzed using transcriptomic profiling, immunofluorescence, ddPCR, WB, apoptosis assays, and transmission electron microscopy (TEM). PUMCH-E13 effectively induced exon 13 skipping in the Rb1 cell line, USH2A-e13 mice (44.44% ± 1.61% reduction), and patient-derived retinal organoids (16.4% ± 4.1% reduction). No significant adverse effects were observed through apoptosis assays or ERG. Additionally, treatment with PUMCH-E13 resulted in the restoration of GPR98 and PDZD7 expression within the USH2 complex, alongside the reorganization of microtubule structures in the photoreceptor cilia. PUMCH-E13 effectively induces exon 13 skipping in USH2A with low toxicity. Additionally, PUMCH-E13 can promote the restoration of photoreceptor cilia structure in patient-derived retinal organoids, revealing its potential therapeutic mechanism.
other
2026-06-11 | Multimodal imaging and intravitreal faricimab for polypoidal choroidal vasculopathy associated with a choroidal nevus in genetically confirmed Usher syndrome type 2: a case report.
Usher syndrome is an autosomal recessive disorder characterized by retinitis pigmentosa (RP), sensorineural hearing loss, and vestibular dysfunction. Polypoidal choroidal vasculopathy (PCV) is characterized by branching neovascular networks and polypoidal lesions. While typically classified within the pachychoroid spectrum, PCV can also manifest in eyes without choroidal thickening. Conversely, RP is usually associated with choroidal thinning, which may lead to underdiagnosis of PCV. To the best of our knowledge, PCV has not previously been reported in patients with Usher syndrome. Here, we present the first genetically confirmed case of Usher syndrome type 2 complicated by PCV that was successfully managed with intravitreal faricimab. A 63-year-old man presented with night blindness. The diagnosis of Usher syndrome type 2 was confirmed based on bilateral RP features, moderate sensorineural hearing loss, and two pathogenic USH2A variants. Six years after the initial diagnosis, the patient developed visual disturbance in the left eye, with the best-corrected visual acuity (BCVA) declining to 20/80. Multimodal imaging, including spectral-domain optical coherence tomography, fluorescein angiography, indocyanine green angiography, and swept-source optical coherence tomography angiography, confirmed the diagnosis of PCV. An amelanotic choroidal nevus was also identified on SD-OCT. After five intravitreal faricimab injections, the BCVA improved to 20/30, with a 75% reduction in pigment epithelial detachment height and complete subretinal fluid resolution without adverse effects. To our knowledge, this is the first reported case of PCV associated with a choroidal nevus in a patient with genetically confirmed Usher syndrome type 2. PCV should not be excluded in patients with RP despite characteristic choroidal thinning. Intravitreal faricimab was effective and well-tolerated, suggesting its therapeutic potential in such cases.
2025-11-28 | Nonsense Mutation in USH2A Exon-13 Activates the Innate Immune Response in Müller Glial Cells
Pathological USH2A mutations cause Usher Syndrome type II, characterized by progres-sive retinitis pigmentosa and hearing and balance impairment. This study aims to inves-tigate the cellular mechanisms underlying USH2A-related retinal degeneration using hu-man induced pluripotent stem cell (hiPSC)-derived retinal organoids. The introduction of a homozygous nonsense mutation in the USH2A hotspot exon-13 resulted in normal photoreceptor development, but loss of ciliary localization of usherin long form B and its interacting proteins, ADGRV1 and whirlin. Notably, single-cell RNA sequencing revealed unexpected significant changes in Müller glial cells (MGCs), with disruptions in the translation, innate immune response, and endolysosomal system. These findings suggest that, while photoreceptor cells are mildly affected by the exon-13 USH2A mutation, MGCs exhibit major dysfunction, potentially contributing to the disease progression and there-fore shedding light on potential alternative therapeutic targets.
2023-11-06 | Outcomes of cochlear implantation in Usher syndrome: a systematic review
Abstract Purpose This study is a systematic review of the literature which seeks to evaluate auditory and quality of life (QOL) outcomes of cochlear implantation in patients with Usher syndrome. Methods Systematic review of studies indexed in Medline via PubMed, Ovid EMBASE, Web of Science, CENTRAL and clinicaltrials.gov was performed up to March 9th 2022, conducted in accordance with the PRISMA statement. Patient demographics, comorbidity, details of cochlear implantation, auditory, and QOL outcomes were extracted and summarized. Results 33 studies reported over 217 cochlear implants in 187 patients with Usher syndrome, comprising subtypes 1 (56 patients), 2 (9 patients), 3 (23 patients), and not specified (99 patients). Auditory outcomes included improved sound detection, speech perception, and speech intelligibility. QOL outcomes were reported for 75 patients, with benefit reported in the majority. Conclusions Many patients with Usher syndrome develop improved auditory outcomes after cochlear implantation with early implantation being an important factor.
2023-06-10 | Generation and Characterization of a Zebrafish Model for ADGRV1-Associated Retinal Dysfunction Using CRISPR/Cas9 Genome Editing Technology
Worldwide, around 40,000 people progressively lose their eyesight as a consequence of retinitis pigmentosa (RP) caused by pathogenic variants in the ADGRV1 gene, for which currently no treatment options exist. A model organism that mimics the human phenotype is essential to unravel the exact pathophysiological mechanism underlying ADGRV1-associated RP, and to evaluate future therapeutic strategies. The introduction of CRISPR/Cas-based genome editing technologies significantly improved the possibilities of generating mutant models in a time- and cost-effective manner. Zebrafish have been recognized as a suitable model to study Usher syndrome-associated retinal dysfunction. Using CRISPR/Cas9 technology we introduced a 4bp deletion in adgrv1 exon 9 (adgrv1rmc22). Immunohistochemical analysis showed that Adgrv1 was absent from the region of the photoreceptor connecting cilium in the adgrv1rmc22 zebrafish retina. Here, the absence of Adgrv1 also resulted in reduced levels of the USH2 complex members usherin and Whrnb, suggesting that Adgrv1 interacts with usherin and Whrnb in zebrafish photoreceptors. When comparing adgrv1rmc22 zebrafish with wild-type controls, we furthermore observed increased levels of aberrantly localized rhodopsin in the photoreceptor cell body, and decreased electroretinogram (ERG) B-wave amplitudes which indicate that the absence of Adgrv1 results in impaired retinal function. Based on these findings we present the adgrv1rmc22 zebrafish as the first ADGRV1 mutant model that displays an early retinal dysfunction. Moreover, the observed phenotypic changes can be used as quantifiable outcome measures when evaluating the efficacy of future novel therapeutic strategies for ADGRV1-associated RP.
2023-01-04 | The adhesion G-protein coupled receptor VLGR1/ADGRV1 controls autophagy
VLGR1/ADGRV1 (very large G protein-coupled receptor-1) is the largest known adhesion G protein-coupled receptor. Mutations in VLGR1/ADGRV1 cause Usher syndrome (USH), the most common form of hereditary deaf-blindness, and have been additionally linked to epilepsy. Although VLGR1/ADGRV1 is almost ubiquitously expressed, little is known about the subcellular function and signalling of the VLGR1 protein and thus about mechanisms underlying the development of diseases. Using affinity proteomics, we have identified key components of autophagosomes as putative interacting proteins of VLGR1. In addition, whole transcriptome sequencing of the retinae of the Vlgr1/del7TM mouse model revealed altered expression profiles of gene-related autophagy. Monitoring autophagy by immunoblotting and immunocytochemistry of the LC3 and p62 as autophagy marker proteins revealed evoked autophagy in VLGR1-deficient hTERT-RPE1 cells and USH2C patient-derived fibroblasts. Our data demonstrate the molecular and functional interaction of VLGR1 with key components of the autophagy process and point to an essential role of VLGR1 in the regulation of autophagy at internal membranes. The close association of VLGR1 with autophagy helps to explain the pathomechanisms underlying human USH and epilepsy-related to VLGR1 defects.
proteins
2026-05-29 | REGULATION OF FORCE TRANSMISSION IN MECHANO-ELECTRICAL TRANSDUCTION CHANNELS OF MAMMALIAN AUDITORY HAIR CELLS
Sound perception relies on specialized actin-based structures called stereocilia, located on the apical surface of auditory hair cells (HCs). Stereocilia are arranged in three rows of increasing height and interconnected with extracellular tip links. Sound-induced vibrations modulate tension on these tip-links, leading to the opening or closing of mechanically gated ion channels that allow cation influx inside the cell, which ultimately generates a neural signal. In recent years, it has been established that the mechano-electrical transduction (MET) channel is constituted by an elaborate complex of multiple proteins associated with the channel itself and with the lower end of the tip-link. However, the molecular and biophysical mechanisms by which external forces are transmitted from the tip-link to the channel are yet unknown, along with the exact role of each protein of MET complex and the plasma membrane in this process. This study represents the first systematic investigation of the MET channel activation in wild type HCs and HCs with deafness-associated variant of Calcium and Integrin-Binding protein 2 (CIB2). CIB2 is essential for hearing and MET in mammalian auditory HCs. CIB2 interacts with TMC1/2, the pore-forming subunits of the MET channel, and is needed for their localization to stereocilia. However, the molecular mechanism by which CIB2 regulates channel activity remains unclear. We generated a mouse model carrying the Cib2 p.R186W mutation that results in deafness but partially preserves MET currents in young postnatal auditory HCs. We found that the p.R186W variant increases resting open probability (Popen) of MET channels and steepens current-displacement relationships, while abolishing fast adaptation and slowing MET channel activation. This phenotype was not observed in Tmc1Δ/Δ OHCs, indicating that it is not due to altered pore identity. Instead, the slowed MET current kinetics and elevated Popen were consistent with loss of phosphatidylinositol 4,5-bisphosphate (PIP2) from stereocilia. The p.R186W mutation also disrupted localization of the membrane-associated protein BAIAP2L2, and electron-dense structures presumably linked to MET complexes. Pharmacological depletion of PIP2 and BAIAP2L2 in wild-type OHCs reproduced the p.R186W MET current phenotype but did not further affect activation and adaptation in Cib2R186W/R186W OHCs. We conclude that CIB2 is required for proper force transmission to MET channels by coordinating BAIAP2L2 and PIP2 localization at the mechanotransduction site. This study addresses three key questions in the auditory field. First, developing an ultra-fast microfabricated actuator for stereocilia bundle deflection allowed, for the first time, to study systematically the molecular mechanisms underlying MET channel activation in the mammalian auditory hair cells. Second, we found that deafness-associated BAIAP2L2 modulates force sensitivity of the MET channels, most likely through its interactions with the plasma membrane. Finally, this work elucidates the molecular consequences of CIB2 mutations underlying Usher syndrome type 1J and non-syndromic deadness DFNB48, which may contribute to the development of future therapeutic treatments of these devasting diseases.
2026-03-11 | Usherin in the pineal gland: altered sleep in zebrafish models of Usher syndrome type 2a
ABSTRACT Usher syndrome type 2A (USH2a), the most common form of hereditary deaf-blindness, is frequently accompanied by fatigue and poor sleep quality. As these sleep problems occur independently of visual decline, it is hypothesized that the USH2A -encoded protein usherin regulates sleep and circadian rhythmicity via an extra-retinal mechanism. Ush2a knockout zebrafish models were utilized to investigate this hypothesis. Immunohistochemical analysis demonstrated usherin localisation in pineal gland photoreceptor cells in wild-type larvae, alongside the USH2 complex proteins Adgrv1 and Whrna. Cross-species transcriptomic and proteomic analyses confirmed USH2A expression in all mammalian pineal gland tissues studied. Circadian clock gene expression was measured over 24 h and showed preserved oscillatory patterns in wild-type and mutant zebrafish. Ex vivo superfusion of pineal glands revealed sustained circadian melatonin release with comparable phase and period to controls, although potential differences in absolute melatonin levels could not be excluded. Despite intact clock gene expression and melatonin release in ush2a mutants, behavioural classification over 24-h recordings revealed altered sleep-wake behaviour: ush2a mutants displayed elevated daytime sleep and significantly prolonged and more variable sleep latency. The dissociation between intact molecular rhythms and abnormal sleep behaviour likely implicates that usherin plays a role in sleep-wake regulation independent of the circadian pacemaker and melatonin synthesis. These findings suggest a novel role of usherin in the pineal gland and establish a mechanistic link between usherin dysfunction and sleep disturbances, providing a biological basis for the fatigue and sleep problems reported in USH2a patients.
2026-01-23 | Compensatory Interplay Between Clarin-1 and Clarin-2 Deafness-Associated Proteins Governs Phenotypic Variability in Hearing.
Usher syndrome type III (USH3) is a genetic disorder characterized by progressive, post-lingual hearing loss, variable vestibular dysfunction, and onset of retinitis pigmentosa. USH3 is caused by mutations in CLRN1, which encodes clarin-1, a tetraspanin-like protein. Mutations in CLRN2, which encodes the related protein clarin-2, are also implicated in progressive, non-syndromic hearing loss in both humans and mice. USH3 patients show considerable phenotypic variability, even among individuals with the same mutation. This variability may result from environmental factors or interactions with other inner ear genes, such as CLRN2. To investigate the functional interplay of these genes, we generated Clrn1- /-Clrn2-/- double knockout mice. RNA-sequencing and functional/physiological analyses revealed that clarin-1 and clarin-2 jointly regulate mechanoelectrical transduction, ionic homeostasis, and synaptic organization. Their combined loss leads to more severe hearing phenotype compared to Clrn1-/- and Clrn2-/- mice, which reveals a functional compensation between them. CLRN2 variants may exacerbate hearing loss in USH3 patients, supporting inclusion of CLRN2 in genetic screening. By revealing a functional, compensatory interplay between clarin-1 and clarin-2, this study reframes CLRN1-associated deafness as a network-dependent disorder and provides a mechanistic basis for genetic stratification and therapeutic directions in USH3 and related sensorineural hearing loss.
2025-04-16 | Tonotopic Specialization of MYO7A Isoforms in Auditory Hair Cells.
1. Mutations in Myo7a cause Usher syndrome type 1B and non-syndromic deafness, but the precise function of MYO7A in sensory hair cells remains unclear. We identify and characterize a novel isoform, MYO7A-N, expressed in auditory hair cells alongside the canonical MYO7A-C. Isoform-specific knock-in mice reveal that inner hair cells primarily express MYO7A-C, while outer hair cells express both isoforms in opposing tonotopic gradients. Both localize 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.
2025-03-22 | H105A peptide eye drops promote photoreceptor survival in murine and human models of retinal degeneration.
Photoreceptor death leads to inherited blinding retinal diseases, such as retinitis pigmentosa (RP). As disease progression often outpaces therapeutic advances, developing effective treatments is urgent. This study evaluates the efficacy of small peptides derived from pigment epithelium-derived factor (PEDF), which are known to restrict common cell death pathways associated with retinal diseases. We tested chemically synthesized peptides (17-mer and H105A) with affinity for the PEDF receptor, PEDF-R, delivered as eye drops to two RP mouse models: rd10 (phosphodiesterase 6b mutation) and RhoP23H/+ (rhodopsin P23H mutation). Additionally, we engineered AAV-H105A vectors for intravitreal delivery in RhoP23H/+ mice. To assess peptide effects in human tissue, we used retinal organoids exposed to cigarette smoke extract, a model of oxidative stress. Photoreceptor survival, morphology and function were evaluated. Here we show that peptides 17-mer and H105A delivered via eye drops successfully reach the retina, promote photoreceptor survival, and improve retinal function in both RP mouse models. Intravitreal delivery of a AAV-H105A vector delays photoreceptor degeneration in RhoP23H/+ mice up to six months. In human retinal organoids, peptide H105A specifically prevents photoreceptor death induced by oxidative stress, a contributing factor to RP progression. PEDF peptide-based eye drops offer a promising, minimally invasive therapy to prevent photoreceptor degeneration in retinal disorders, with a favorable safety profile.
gene therapies
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.
2026-07-03 | Subretinal injection in the USH1CR31∗ pig model leads to chorioretinal atrophy that limits evaluation of efficacy of an AAV-mediated gene therapy.
Usher syndrome (USH) is the most common form of hereditary deaf-blindness. There is no effective treatment for vision loss to date. Here we aimed to evaluate AAV-mediated ocular gene therapy for USH1C in pigs. USH1CR31∗ and wild type (WT) pigs were bilaterally subretinal injected with 200 μL of 1∗1011 vg/eye Anc80 AAV vectors expressing USH1C_a1 under the control of either a rod-specific human rhodopsin kinase (GRK1) promoter, a ubiquitous promoter (CAG), or vehicle control. Retinal structure and function were assessed by optical coherence tomography and electroretinography (ERG) at baseline and every six months post-injection. Decreased ERG amplitudes and reduction of total retinal thickness were observed in all groups following surgery. At 18 months post-injection, animals were sacrificed and treated and untreated retinal regions were analyzed by qRT-PCR, Western blots, pathohistological examinations, and immunohistochemistry. Both vectors resulted in high levels of USH1C_a1 transcript expression, but only slightly increased harmonin protein expression in USH1CR31∗ pigs. Across all treatment groups, chorioretinal atrophy (CRA) was observed, accompanied by reduced retinal thickness and increased GFAP expression. In conclusion, both vectors achieved efficient retinal transgene delivery in USH1CR31∗ pigs. However, CRA developed in all groups, even in vehicle-injected controls. The extensive retinal damage associated with CRA has likely masked a potentially beneficial therapeutic effect. For future translational development, optimization of dosing, and modifications in surgical technique will be of crucial importance.
2026-07-02 | Müller Glia-Exclusive CLRN1 Expression Drives Non-Cell-Autonomous Photoreceptor Degeneration in Usher Syndrome Type 3A.
Usher syndrome type 3A (USH3A), caused by CLRN1 mutations, leads to progressive deaf-blindness. Although CLRN1 expression has been localized to Müller glia (MG), the pathogenic mechanisms linking glial CLRN1 deficiency to photoreceptor death remain undefined. We utilized a novel large-animal model to elucidate cell-type-specific pathogenesis at single-nucleus resolution. CLRN1-/- rabbits were generated via CRISPR/Cas9. Retinal phenotyping included longitudinal optical coherence tomography (OCT), electroretinography (ERG), and histology for up to 3 years. Single-nucleus RNA sequencing (snRNA-seq) was performed at a pre-symptomatic stage (10 months, n = 3/genotype). Differentially expressed genes (DEGs) were identified using pseudobulk DESeq2 and validated via immunofluorescence. CLRN1-/- rabbits exhibited progressive outer nuclear layer thinning and delayed ERG responses starting after 20 months, mimicking human clinical kinetics. The snRNA-seq revealed that CLRN1 is exclusively expressed in a discrete subset (∼24%) of MG. Mutant MG exhibited transcriptomic downregulation of the adherens junction component CTNNA2, which was validated at the protein level by immunofluorescence staining. Photoreceptors exhibit extensive non-cell-autonomous dysregulation (232 rod and 68 cone DEGs) characterized by loss of the cone synaptic organizer TENM2 and rod-specific splicing dysregulation (CWF19L2). Concurrently, inner retinal neurons mounted a robust proteostatic response via HSP90 family upregulation (HSP90AB1, HSP90AA1, HSP90B1), a defensive signature absent in vulnerable photoreceptors. Our findings suggest an "anchor-shield" mechanism: MG CLRN1 loss compromises the outer limiting membrane (OLM) adhesion complex ("anchor"), and photoreceptors lack the proteostatic response ("shield") seen in resilient inner neurons. Restoring CLRN1 in Müller glia or implementing photoreceptor neuroprotection represents promising therapeutic strategies for USH3A.
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.
2026-01-15 | Reclassification of a novel NR2E3 variant as likely pathogenic: a case report of autosomal recessive RP37 in siblings.
NR2E3 is a nuclear orphan receptor essential for photoreceptor development. Variants in the NR2E3 gene are associated with autosomal recessive retinitis pigmentosa 37 (RP37) and enhanced S-cone syndrome (ESCS). We report a novel NR2E3 variant in a family with RP37, aiming to clarify pathogenicity through clinical and genetic evaluation. The proband, a 26-year-old woman, experienced childhood-onset nyctalopia and progressive vision loss. Fundus exam revealed mid-peripheral pigment clumps and parafoveal depigmentation. Fundus autofluorescence showed widespread hypo-autofluorescent lesions; spectral-domain OCT identified outer nuclear layer thinning and ellipsoid zone loss. Full-field electroretinography confirmed severely diminished scotopic and photopic responses. Her 23-year-old sister had milder pigmentary changes and cystoid macular edema, while their 20-year-old brother's phenotype was less pronounced. All three siblings were homozygous for a novel missense variant in NR2E3 (NM_014249.4:c.352 G > C; p.Val118Leu), located within the DNA-binding domain. Both parents were heterozygous carriers. A previously reported variant affecting the same codon but resulting in a different amino acid change, along with its elevated allele frequency in East Asian populations, suggests a founder effect and supports its pathogenic potential. This report supports reclassifying NR2E3 c.352 G > C (NM_014249.4) as likely pathogenic. A comprehensive genotype-phenotype analysis remains essential for advancing our understanding of NR2E3-associated retinal dystrophies.
small molecules
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.
2026-07-10 | 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.
2026-05-20 | Histidine Supplementation Stabilizes Hearing and Vision and Improves Growth in HARS1-Related Autosomal Recessive Disorder Associated With Usher-Like Symptoms.
Autosomal recessive HARS1-related disorder (originally described as Usher syndrome type 3B) caused by a homozygous Y454S variant in the histidyl-tRNA synthetase gene (HARS1) is characterized by progressive sensorineural hearing and vision loss and respiratory deterioration with risk for sudden death following febrile illnesses. In-vitro studies have previously shown that histidine can rescue a humanized yeast model for pathogenic HARS alleles. Fourteen children homozygous for HARS Y454S were treated with supplemental oral histidine (50 mg/kg BID) and monitored with bloodwork and physical, visual, and audiometry assessments during a 3-year clinical trial, then followed for more than 4 years on histidine in the post-trial period. Patient fibroblasts were assessed for response to histidine. Hearing and vision remained stable, and growth improved significantly. Children remained healthy, with no severe deteriorations despite exposure to bacterial and viral infections, including COVID-19. Gains in growth were maintained in the post-trial period on varying levels of histidine supplementation. Daily oral histidine supplementation in children with autosomal recessive HARS1-related disorder can ameliorate or slow the progression of disease and is safe, inexpensive, and well tolerated. This study adds to the growing list of autosomal recessive ARSopathies (aminoacyl-tRNA synthetase disorders) that are amenable to amino acid supplementation.
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.
2025-05-27 | Advancing Therapeutic Strategies for Nonsense-Related Diseases: From Small Molecules to Nucleic Acid-Based Innovations.
Nonsense mutations in gene coding regions introduce an in-frame premature termination codon (PTC) in the mRNA transcript, resulting in the early termination of translation and the production of a truncated, nonfunctional protein. The absence of protein expression and the consequent loss of essential cellular functions are responsible for the severe phenotypes in the so-called genetic nonsense-related diseases (NRDs), such as cystic fibrosis, hemophilia, Duchenne muscular dystrophy, Fabry disease, Choroideremia, Usher syndrome, Shwachman-Diamond syndrome, and even certain types of cancer. Nonsense mutations pose a significant challenge in the treatment of NRDs, as a specific approach directly addressing this genetic defect is currently unavailable. Developing new therapeutic strategies for nonsense suppression is a crucial goal of precision medicine. This review describes some of the most promising therapeutic approaches and emerging strategies for treating NRDs. It considered both the use of small molecules to interfere with molecular mechanisms related to nonsense mutations, such as translational readthrough-inducing drugs (TRIDs) or inhibitors of the nonsense-mediated decay (NMD) pathway, and also innovative approaches involving nucleic acids, such as gene editing, anticodon engineered-tRNA (ACE-tRNA), or mRNA-based therapy. Future research should focus on refining these approaches and exploring integrated and personalized treatments to enhance therapeutic outcomes and ensure continuous improvement in the quality of care.
oligonucleotides
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.
2026-04-28 | 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.
2025-09-25 | AAV-mediated exon skipping therapy for Usher syndrome, type 2A.
Usher syndrome can cause loss of vision, hearing, and balance. There are four clinical subtypes, USH1-4, which are associated with mutations in genes important for structure, function, and survival of photoreceptor cells in the retina and sensory hair cells in the inner ear. Genetic mutations in the USH2A gene, which encodes usherin protein, are the most common cause of Usher syndrome worldwide, with c.2299delG (p.Glu767Serfs∗21) being the most frequent pathogenic variant. An investigational antisense oligonucleotide (ASO) for USH2A c.2299delG, QR-421a, designed to bypass the mutation, has already shown promise in phase 1/2 clinical trials. While recently developed chemistry provides longer ASO half-lives, repeated injection of ASOs may be required to provide long-term efficacy. To overcome this limitation, we screened novel USH2A exon 13 skippers and 20 AAV capsids with the goal of developing a vectorized ASO exon skipping strategy. Optimized vectors and skippers were evaluated in inner ear and retinal organoids derived from human stem cell lines bearing the USH2A c.2299delG mutation. The data revealed enhanced skipping of the pathogenic exon, offering an alternative strategy for treatment of USH2A patients using a single local injection which may prevent progression of vision and hearing loss.
2025-09-19 | Exon Skipping Therapy Restores Ciliary Function in USH2A-Related Retinal Degeneration.
This study aimed to evaluate the exon-skipping efficacy and safety of an antisense oligonucleotide (AON) targeting USH2A exon 13 across multiple models, including the Rb1 cell line, humanized USH2A-e13 transgenic mice, and patient-derived retinal organoids. Additionally, we investigated the pathogenic mechanisms of USH2A variants and the therapeutic effects of exon skipping on photoreceptor cilia structure and function. Bioinformatic tools were used to design AONs targeting USH2A exon 13, and their exon-skipping efficiency was assessed at both RNA and protein levels in Rb1 cells. A humanized USH2A-e13 transgenic mouse model was generated via gene editing and received intravitreal AON injections. Retinal distribution, exon-skipping efficiency, and toxicity were evaluated through fundus fluorescence imaging, immunofluorescence staining, droplet digital PCR (ddPCR), Western blot (WB), apoptosis assays, and electroretinography (ERG). Patient-derived induced pluripotent stem cells (iPSCs) were differentiated into retinal organoids and analyzed using transcriptomic profiling, immunofluorescence, ddPCR, WB, apoptosis assays, and transmission electron microscopy (TEM). PUMCH-E13 effectively induced exon 13 skipping in the Rb1 cell line, USH2A-e13 mice (44.44% ± 1.61% reduction), and patient-derived retinal organoids (16.4% ± 4.1% reduction). No significant adverse effects were observed through apoptosis assays or ERG. Additionally, treatment with PUMCH-E13 resulted in the restoration of GPR98 and PDZD7 expression within the USH2 complex, alongside the reorganization of microtubule structures in the photoreceptor cilia. PUMCH-E13 effectively induces exon 13 skipping in USH2A with low toxicity. Additionally, PUMCH-E13 can promote the restoration of photoreceptor cilia structure in patient-derived retinal organoids, revealing its potential therapeutic mechanism.
other
2026-06-11 | Multimodal imaging and intravitreal faricimab for polypoidal choroidal vasculopathy associated with a choroidal nevus in genetically confirmed Usher syndrome type 2: a case report.
Usher syndrome is an autosomal recessive disorder characterized by retinitis pigmentosa (RP), sensorineural hearing loss, and vestibular dysfunction. Polypoidal choroidal vasculopathy (PCV) is characterized by branching neovascular networks and polypoidal lesions. While typically classified within the pachychoroid spectrum, PCV can also manifest in eyes without choroidal thickening. Conversely, RP is usually associated with choroidal thinning, which may lead to underdiagnosis of PCV. To the best of our knowledge, PCV has not previously been reported in patients with Usher syndrome. Here, we present the first genetically confirmed case of Usher syndrome type 2 complicated by PCV that was successfully managed with intravitreal faricimab. A 63-year-old man presented with night blindness. The diagnosis of Usher syndrome type 2 was confirmed based on bilateral RP features, moderate sensorineural hearing loss, and two pathogenic USH2A variants. Six years after the initial diagnosis, the patient developed visual disturbance in the left eye, with the best-corrected visual acuity (BCVA) declining to 20/80. Multimodal imaging, including spectral-domain optical coherence tomography, fluorescein angiography, indocyanine green angiography, and swept-source optical coherence tomography angiography, confirmed the diagnosis of PCV. An amelanotic choroidal nevus was also identified on SD-OCT. After five intravitreal faricimab injections, the BCVA improved to 20/30, with a 75% reduction in pigment epithelial detachment height and complete subretinal fluid resolution without adverse effects. To our knowledge, this is the first reported case of PCV associated with a choroidal nevus in a patient with genetically confirmed Usher syndrome type 2. PCV should not be excluded in patients with RP despite characteristic choroidal thinning. Intravitreal faricimab was effective and well-tolerated, suggesting its therapeutic potential in such cases.
2025-11-28 | Nonsense Mutation in USH2A Exon-13 Activates the Innate Immune Response in Müller Glial Cells
Pathological USH2A mutations cause Usher Syndrome type II, characterized by progres-sive retinitis pigmentosa and hearing and balance impairment. This study aims to inves-tigate the cellular mechanisms underlying USH2A-related retinal degeneration using hu-man induced pluripotent stem cell (hiPSC)-derived retinal organoids. The introduction of a homozygous nonsense mutation in the USH2A hotspot exon-13 resulted in normal photoreceptor development, but loss of ciliary localization of usherin long form B and its interacting proteins, ADGRV1 and whirlin. Notably, single-cell RNA sequencing revealed unexpected significant changes in Müller glial cells (MGCs), with disruptions in the translation, innate immune response, and endolysosomal system. These findings suggest that, while photoreceptor cells are mildly affected by the exon-13 USH2A mutation, MGCs exhibit major dysfunction, potentially contributing to the disease progression and there-fore shedding light on potential alternative therapeutic targets.
2023-11-06 | Outcomes of cochlear implantation in Usher syndrome: a systematic review
Abstract Purpose This study is a systematic review of the literature which seeks to evaluate auditory and quality of life (QOL) outcomes of cochlear implantation in patients with Usher syndrome. Methods Systematic review of studies indexed in Medline via PubMed, Ovid EMBASE, Web of Science, CENTRAL and clinicaltrials.gov was performed up to March 9th 2022, conducted in accordance with the PRISMA statement. Patient demographics, comorbidity, details of cochlear implantation, auditory, and QOL outcomes were extracted and summarized. Results 33 studies reported over 217 cochlear implants in 187 patients with Usher syndrome, comprising subtypes 1 (56 patients), 2 (9 patients), 3 (23 patients), and not specified (99 patients). Auditory outcomes included improved sound detection, speech perception, and speech intelligibility. QOL outcomes were reported for 75 patients, with benefit reported in the majority. Conclusions Many patients with Usher syndrome develop improved auditory outcomes after cochlear implantation with early implantation being an important factor.
2023-06-10 | Generation and Characterization of a Zebrafish Model for ADGRV1-Associated Retinal Dysfunction Using CRISPR/Cas9 Genome Editing Technology
Worldwide, around 40,000 people progressively lose their eyesight as a consequence of retinitis pigmentosa (RP) caused by pathogenic variants in the ADGRV1 gene, for which currently no treatment options exist. A model organism that mimics the human phenotype is essential to unravel the exact pathophysiological mechanism underlying ADGRV1-associated RP, and to evaluate future therapeutic strategies. The introduction of CRISPR/Cas-based genome editing technologies significantly improved the possibilities of generating mutant models in a time- and cost-effective manner. Zebrafish have been recognized as a suitable model to study Usher syndrome-associated retinal dysfunction. Using CRISPR/Cas9 technology we introduced a 4bp deletion in adgrv1 exon 9 (adgrv1rmc22). Immunohistochemical analysis showed that Adgrv1 was absent from the region of the photoreceptor connecting cilium in the adgrv1rmc22 zebrafish retina. Here, the absence of Adgrv1 also resulted in reduced levels of the USH2 complex members usherin and Whrnb, suggesting that Adgrv1 interacts with usherin and Whrnb in zebrafish photoreceptors. When comparing adgrv1rmc22 zebrafish with wild-type controls, we furthermore observed increased levels of aberrantly localized rhodopsin in the photoreceptor cell body, and decreased electroretinogram (ERG) B-wave amplitudes which indicate that the absence of Adgrv1 results in impaired retinal function. Based on these findings we present the adgrv1rmc22 zebrafish as the first ADGRV1 mutant model that displays an early retinal dysfunction. Moreover, the observed phenotypic changes can be used as quantifiable outcome measures when evaluating the efficacy of future novel therapeutic strategies for ADGRV1-associated RP.
2023-01-04 | The adhesion G-protein coupled receptor VLGR1/ADGRV1 controls autophagy
VLGR1/ADGRV1 (very large G protein-coupled receptor-1) is the largest known adhesion G protein-coupled receptor. Mutations in VLGR1/ADGRV1 cause Usher syndrome (USH), the most common form of hereditary deaf-blindness, and have been additionally linked to epilepsy. Although VLGR1/ADGRV1 is almost ubiquitously expressed, little is known about the subcellular function and signalling of the VLGR1 protein and thus about mechanisms underlying the development of diseases. Using affinity proteomics, we have identified key components of autophagosomes as putative interacting proteins of VLGR1. In addition, whole transcriptome sequencing of the retinae of the Vlgr1/del7TM mouse model revealed altered expression profiles of gene-related autophagy. Monitoring autophagy by immunoblotting and immunocytochemistry of the LC3 and p62 as autophagy marker proteins revealed evoked autophagy in VLGR1-deficient hTERT-RPE1 cells and USH2C patient-derived fibroblasts. Our data demonstrate the molecular and functional interaction of VLGR1 with key components of the autophagy process and point to an essential role of VLGR1 in the regulation of autophagy at internal membranes. The close association of VLGR1 with autophagy helps to explain the pathomechanisms underlying human USH and epilepsy-related to VLGR1 defects.
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
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. |
Let's accelerate rare disease drug discovery
Let's accelerate drug discovery
Get access to Explority AI’s forecasts to outperform average preclinical success rates. Whether you’re expanding your R&D pipeline, evaluating a partnership, or simply have a question — we’d love to hear from you.