ArticleMolecular therapy. Nucleic acids2016
Antisense Oligonucleotide Mediated Splice Correction of a Deep Intronic Mutation in OPA1.
Article in Molecular therapy. Nucleic acids, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
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Who cites it
30 citing papers in PubMed, 49 citations in OpenAlex.
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- Preclinical assessment of splicing modulation therapy for ABCA4 variant c.768G>T in Stargardt disease.Communications medicine · 2025Article
- Efficacy, biodistribution and safety comparison of chemically modified antisense oligonucleotides in the retina.Nucleic acids research · 2024Article
- Alternative RNA Splicing in the Retina: Insights and Perspectives.Cold Spring Harbor perspectives in medicine · 2023Review
- Detailed analysis of an enriched deep intronic ABCA4 variant in Irish Stargardt disease patients.Scientific reports · 2023Article
- Antisense oligonucleotide therapy corrects splicing in the common Stargardt disease type 1-causing variantMolecular therapy. Nucleic acids · 2023Article
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- The Predicted Splicing Variant c.11+5G>A inCells · 2022Article
- Panel-based next-generation sequencing identifies novel mutations in Bulgarian patients with inherited retinal dystrophies.Molecular genetics & genomic medicine · 2022Article
- Preparing n-of-1 Antisense Oligonucleotide Treatments for Rare Neurological Diseases in Europe: Genetic, Regulatory, and Ethical Perspectives.Nucleic acid therapeutics · 2022Article
- Antisense RNA Therapeutics: A Brief Overview.Methods in molecular biology (Clifton, N.J.) · 2022Article
- An Overview of the Genetics ofGenes · 2021Review
- Antisense Oligonucleotide-Based Rescue of Aberrant Splicing Defects Caused by 15 Pathogenic Variants inInternational journal of molecular sciences · 2021Article
- The Alter Retina: Alternative Splicing of Retinal Genes in Health and Disease.International journal of molecular sciences · 2021Review
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- Gene Therapy in Inherited Retinal Diseases: An Update on Current State of the Art.Frontiers in medicine · 2021Review
- Stereochemistry Enhances Potency, Efficacy, and Durability ofTranslational vision science & technology · 2021Article
- Mutation-Directed Therapeutics for Neurofibromatosis Type I.Molecular therapy. Nucleic acids · 2020Review
Corrections and comments
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Authors and funding
7 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Inherited optic neuropathies (ION) present an important cause of blindness in the European working-age population. Recently we reported the discovery of four independent families with deep intronic mutations in the main inherited optic neuropathies gene OPA1. These deep intronic mutations cause mis-splicing of the OPA1 pre-messenger-RNA transcripts by creating cryptic acceptor splice sites. As a rescue strategy we sought to prevent mis-splicing of the mutant pre-messenger-RNA by applying 2'O-methyl-antisense oligonucleotides (AONs) with a full-length phosphorothioate backbone that target the cryptic acceptor splice sites and the predicted novel branch point created by the deep intronic mutations, respectively. Transfection of patient-derived primary fibroblasts with these AONs induced correct splicing of the mutant pre-messenger-RNA in a time and concentration dependent mode of action, as detected by pyrosequencing of informative heterozygous variants. The treatment showed strong rescue effects (~55%) using the cryptic acceptor splice sites targeting AON and moderate rescue (~16%) using the branch point targeting AON. The highest efficacy of Splice correction could be observed 4 days after treatment however, significant effects were still seen 14 days post-transfection. Western blot analysis revealed increased amounts of OPA1 protein with maximum amounts at ~3 days post-treatment. In summary, we provide the first mutation-specific in vitro rescue strategy for OPA1 deficiency using synthetic AONs.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.