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PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

PURPOSE: In the past, cochlear implantation (CI) was not commonly offered to this population due to concerns about limited auditory rehabilitation outcomes. Recent advancements in CI technology and multidisciplinary rehabilitation have expanded candidacy, but outcomes in deafblind patients remain underexplored. This systematic review and meta-analysis aimed to synthesize available evidence on CI outcomes in deafblind individuals. METHODS: Data sources included PubMed, Web of Science, Scopus, and Cochrane Library from inception to July 20, 2025. Observational studies included adults or children with confirmed dual sensory impairment after CI. Primary outcomes included speech clarity (Speech Intelligibility Rating [SIR]), verbal communication ability, and telephone communication competence. Secondary outcomes encompassed audiological performance, auditory and cognitive development, educational integration, psychological benefits, and advanced auditory skills. Risk of bias was examined using the NIH Quality Assessment Tool and Newcastle-Ottawa Scale. STATA 18 was used to perform random-effects meta-analyses. RESULTS: Thirty-six studies were analyzed, including 491 patients (mean age 23.68 years; 23% male). The pooled mean SIR score was 3.45 (95% CI: 2.69-4.21), with no significant difference between Usher and non-Usher groups (p = 0. 52). Verbal communication ability was achieved in 70% (95% CI: 0.60-0.79), while telephone communication competence was limited to 51% (95% CI: 0.33-0.69). CONCLUSION: Cochlear implantation is an effective intervention for deafblind individuals, demonstrating significant improvements in speech intelligibility and verbal communication regardless of the underlying etiology (Usher vs. non-Usher). While verbal communication rates are promising, advanced skills such as telephone competence remain limited, suggesting the need for continued multidisciplinary rehabilitation.

Pathogenic variation of SLC26A4 gene causes both Pendred syndrome (PDS) and non-syndromic enlarged vestibular aqueduct (NSEVA/DFNB4), two autosomal recessive disorders. The former accounts for approximately 6% of human genetic hearing loss, making it the second most common form of syndromic deafness after Usher syndrome, while the latter is the most common radiological malformation associated with childhood sensorineural hearing loss (SNHL). Here, we used short- and long-read single-cell RNA sequencing (scRNA-seq) of pendrin-expressing cells in the murine cochlea to identify a novel short isoform of Slc26a4. We demonstrate that the short Slc26a4 isoform is expressed in both the inner ear and kidney and investigate its interactions and functions. We also characterize the genotype-phenotype association for SLC26A4-related hearing loss in the context of these two isoforms. These results provide a new reference for molecular profiling of pendrin and offer novel insights into cell-type-specific splicing events and SLC26A4-related hearing loss.

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.

Variants of the WHRN/DFNB31 gene cause Usher syndrome type 2D (USH2D), a rare subtype of Usher syndrome. Usher syndrome is an autosomal recessive disorder characterized by sensorineural hearing loss and progressive retinal degeneration due to retinitis pigmentosa. We report the case of a 63-year-old woman with clinical and genetic findings consistent with USH2D. Ophthalmic evaluation demonstrated reduced visual acuity, bilateral optic disc pallor, mid-peripheral bony spicules, vascular attenuation, and macular abnormalities. Full-field electroretinography showed non-recordable photopic and scotopic responses bilaterally, consistent with extinguished rod and cone responses. Macular optical coherence tomography demonstrated a central subfield thickness of 220 µm (oculus dexter or right eye (OD)) and 235 µm (oculus sinister or left eye (OS)), a cube volume of 7.8 mm³ OD and 6.5 mm³ OS, and an average cube thickness of 215 µm OD and 180 µm OS, supporting structural macular involvement. Electrooculography demonstrated an abnormal Arden ratio of 1.58 in both eyes, consistent with retinal pigment epithelium dysfunction. Based on these ocular findings, the patient was diagnosed with retinitis pigmentosa. Genetic testing with next-generation sequencing identified a homozygous pathogenic WHRN c.74dup (p.Gly26Argfs*153) variant. To our knowledge, this specific frameshift variant has not been previously reported in the literature in affected individuals with WHRN-related disease. This case highlights the importance of genetic testing and multimodal ophthalmic evaluation in patients with inherited retinal dystrophies and contributes to the limited literature describing Usher syndrome due to WHRN mutations.