ArticleInvestigative ophthalmology & visual science2025
Exon Skipping Therapy Restores Ciliary Function in USH2A-Related Retinal Degeneration.
Article in Investigative ophthalmology & visual science, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Purpose: 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. Methods: 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). Results: 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. Conclusions: 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.
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