ArticleMolecular therapy. Nucleic acids2020
Antisense Oligonucleotide- and CRISPR-Cas9-Mediated Rescue of mRNA Splicing for a Deep Intronic CLRN1 Mutation.
Article in Molecular therapy. Nucleic acids, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 30 citations in OpenAlex.
- AAV-mediated exon skipping therapy for Usher syndrome, type 2A.Molecular therapy : the journal of the American Society of Gene Therapy · 2026Article
- Exosome-Mediated Regulation of Aerobic Glycolysis in Hepatocellular Carcinoma: Mechanisms and Therapeutic Implications.Journal of hepatocellular carcinoma · 2026Review
- Decoding retinitis pigmentosa: molecular targets and therapy with focus on pre-mRNA splicing.Cellular and molecular life sciences : CMLS · 2025Review
- Alternative Splicing Dysregulation in Retinitis Pigmentosa: Pathogenic Mechanisms and Therapeutic Opportunities.Biomolecules · 2025Review
- Antisense oligonucleotide therapy for patients with Friedreich's ataxia carrying the c.165+5G>C splicing mutation.Molecular therapy. Nucleic acids · 2025Article
- ALKBH3-Mediated MAdvanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- A review of the 661W cell line as a tool to facilitate treatment development for retinal diseases.Cell & bioscience · 2025Review
- Expansion of Splice-Switching Therapy with Antisense Oligonucleotides.International journal of molecular sciences · 2025Review
- Current approaches for Usher syndrome disease models and developing therapies.Frontiers in cell and developmental biology · 2025Review
- Lipopeptide-mediated Cas9 RNP delivery: A promising broad therapeutic strategy for safely removing deep-intronic variants inMolecular therapy. Nucleic acids · 2024Article
- A Leaky Deep Intronic Splice Variant inGenes · 2024Article
- Recent Therapeutic Progress and Future Perspectives for the Treatment of Hearing Loss.Biomedicines · 2023Review
- Alternative splicing in shaping the molecular landscape of the cochlea.Frontiers in cell and developmental biology · 2023Review
- Antisense oligonucleotides targeting exon 11 are able to partially rescue the NF2-related schwannomatosis phenotypeMolecular therapy. Nucleic acids · 2022Article
- dCas9-VPR-mediated transcriptional activation of functionally equivalent genes for gene therapy.Nature protocols · 2022Review
- From Bench to Bed: The Current Genome Editing Therapies for Glaucoma.Frontiers in cell and developmental biology · 2022Review
- Antisense Oligonucleotide-Mediated Exon-skipping Therapies: Precision Medicine Spreading from Duchenne Muscular Dystrophy.JMA journal · 2021Review
- The Challenges and Strategies of Antisense Oligonucleotide Drug Delivery.Biomedicines · 2021Review
- Toward the Treatment of Inherited Diseases of the Retina Using CRISPR-Based Gene Editing.Frontiers in medicine · 2021Review
Corrections and comments
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Authors and funding
11 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Mutations in CLRN1 cause Usher syndrome (USH) type III (USH3A), a disease characterized by progressive hearing impairment, retinitis pigmentosa, and vestibular dysfunction. Due to the lack of appropriate disease models, no efficient therapy for retinitis pigmentosa in USH patients exists so far. In addition, given the yet undefined functional role and expression of the different CLRN1 splice isoforms in the retina, non-causative therapies such as gene supplementation are unsuitable at this stage. In this study, we focused on the recently identified deep intronic c.254-649T>G CLRN1 splicing mutation and aimed to establish two causative treatment approaches: CRISPR-Cas9-mediated excision of the mutated intronic region and antisense oligonucleotide (AON)-mediated correction of mRNA splicing. The therapeutic potential of these approaches was validated in different cell types transiently or stably expressing CLRN1 minigenes. Both approaches led to substantial correction of the splice defect. Surprisingly, however, no synergistic effect was detected when combining both methods. Finally, the injection of naked AONs into mice expressing the mutant CLRN1 minigene in the retina also led to a significant splice rescue. We propose that both AONs and CRISPR-Cas9 are suitable strategies to initiate advanced preclinical studies for treatment of USH3A patients.
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