ArticleJournal of cystic fibrosis : official journal of the European Cystic Fibrosis Society2021
Antisense oligonucleotide-based drug development for Cystic Fibrosis patients carrying the 3849+10 kb C-to-T splicing mutation.
Article in Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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25 citing papers in PubMed, 50 citations in OpenAlex.
- Upregulation of a CFTR mRNA isoform has therapeutic potential for the treatment of 3' CFTR PTC variants.Molecular therapy. Nucleic acids · 2026Article
- A rare 5'UTR variant in SEC24D reveals translational dysfunction in osteogenesis imperfecta: a roadmap for RNA therapeutic rescue.Scientific reports · 2026Article
- Progress of siRNA Nanomedicines in Modulating the Microenvironment of Triple-Negative Breast Cancer.International journal of nanomedicine · 2026Review
- Noncoding DNA Variants in Primary Ciliary Dyskinesia: Another Piece of the Diagnostic Puzzle.American journal of respiratory and critical care medicine · 2025Article
- Progress of personalized medicine of cystic fibrosis in the times of efficient CFTR modulators.Molecular and cellular pediatrics · 2025Review
- RNA splicing: Novel star in pulmonary diseases with a treatment perspective.Acta pharmaceutica Sinica. B · 2025Review
- Mechanism of Genome Editing Tools and Their Application on Genetic Inheritance Disorders.Global medical genetics · 2024Review
- Splice modulation strategy applied to deep intronic variants inProceedings of the National Academy of Sciences of the United States of America · 2024Article
- Functional Consequences of CFTR Interactions in Cystic Fibrosis.International journal of molecular sciences · 2024Review
- Cystic fibrosis management in pediatric population-from clinical features to personalized therapy.Frontiers in pediatrics · 2024Review
- Gene, RNA, and ASO-based therapeutic approaches in Cystic Fibrosis.Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society · 2023Article
- Antisense Oligonucleotide Therapeutics for Cystic Fibrosis: Recent Developments and Perspectives.Molecules and cells · 2023Review
- What Can RNA-Based Therapy Do for Monogenic Diseases?Pharmaceutics · 2023Review
- Features of CFTR mRNA and implications for therapeutics development.Frontiers in genetics · 2023Review
- Oligonucleotide-based therapies for cystic fibrosis.Current opinion in pharmacology · 2022Review
- Advances in Preclinical In Vitro Models for the Translation of Precision Medicine for Cystic Fibrosis.Journal of personalized medicine · 2022Review
- Splicing mutations in the CFTR gene as therapeutic targets.Gene therapy · 2022Review
- Molecular mechanisms of cystic fibrosis - how mutations lead to misfunction and guide therapy.Bioscience reports · 2022Review
- One Size Does Not Fit All: The Past, Present and Future of Cystic Fibrosis Causal Therapies.Cells · 2022Review
- Exon-skipping antisense oligonucleotides for cystic fibrosis therapy.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
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Authors and funding
18 authors at 7 institutions in 5 countries.
Funding
Abstract
backgroundAntisense oligonucleotide (ASO)-based drugs for splicing modulation were recently approved for various genetic diseases with unmet need. Here we aimed to develop an ASO-based splicing modulation therapy for Cystic Fibrosis (CF) patients carrying the 3849+10 kb C-to-T splicing mutation in the CFTR gene.
methodsWe have screened, in FRT cells expressing the 3849+10 kb C-to-T splicing mutation, ~30 2'-O-Methyl-modified phosphorothioate ASOs, targeted to prevent the recognition and inclusion of a cryptic exon generated due to the mutation. The effect of highly potent ASO candidates on the splicing pattern, protein maturation and CFTR function was further analyzed in well differentiated primary human nasal and bronchial epithelial cells, derived from patients carrying at least one 3849+10 kb C-to-T allele.
resultsA highly potent lead ASO, efficiently delivered by free uptake, was able to significantly increase the level of correctly spliced mRNA and completely restore the CFTR function to wild type levels in cells from a homozygote patient. This ASO led to CFTR function with an average of 43% of wild type levels in cells from various heterozygote patients. Optimized efficiency of the lead ASO was further obtained with 2'-Methoxy Ethyl modification (2'MOE).
conclusionThe highly efficient splicing modulation and functional correction, achieved by free uptake of the selected lead ASO in various patients, demonstrate the ASO therapeutic potential benefit for CF patients carrying splicing mutations and is aimed to serve as the basis for our current clinical development.
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