ArticleInvestigative ophthalmology & visual science2013
Allele-specific siRNA silencing for the common keratin 12 founder mutation in Meesmann epithelial corneal dystrophy.
Article in Investigative ophthalmology & visual science, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 40 citations in OpenAlex.
- Meesmann Corneal Dystrophy with Epithelial Basement Membrane Abnormalities: Clinical and Genetic Analysis of Two Families with Novel and Known Mutations inInternational journal of molecular sciences · 2026Article
- A Novel Pathogenic Variant in theJournal of clinical medicine · 2025Article
- Innovative Therapeutic Approaches for the Treatment of the Ocular Morbidities in Patients with EEC Syndrome.Cells · 2023Review
- Tribology and the Ocular Surface.Clinical ophthalmology (Auckland, N.Z.) · 2022Review
- Development of a Corneal Bioluminescence Mouse for Real-Time In Vivo Evaluation of Gene Therapies.Translational vision science & technology · 2020Article
- Effective In Vivo Topical Delivery of siRNA and Gene Silencing in Intact Corneal Epithelium Using a Modified Cell-Penetrating Peptide.Molecular therapy. Nucleic acids · 2019Article
- Article
- Towards personalised allele-specific CRISPR gene editing to treat autosomal dominant disorders.Scientific reports · 2017Article
- ASPsiRNA: A Resource of ASP-siRNAs Having Therapeutic Potential for Human Genetic Disorders and Algorithm for Prediction of Their Inhibitory Efficacy.G3 (Bethesda, Md.) · 2017Article
- Allele-specific silencing of EEC p63 mutant R304W restores p63 transcriptional activity.Cell death & disease · 2016Article
- Keratin 12 missense mutation induces the unfolded protein response and apoptosis in Meesmann epithelial corneal dystrophy.Human molecular genetics · 2016Article
- Non-Invasive Intravital Imaging of siRNA-Mediated Mutant Keratin Gene Repression in Skin.Molecular imaging and biology · 2016Article
- CRISPR/Cas9 DNA cleavage at SNP-derived PAM enables both in vitro and in vivo KRT12 mutation-specific targeting.Gene therapy · 2016Article
- High-Throughput Screening for Drugs that Modulate Intermediate Filament Proteins.Methods in enzymology · 2016Article
- PKC412 normalizes mutation-related keratin filament disruption and hepatic injury in mice by promoting keratin-myosin binding.Hepatology (Baltimore, Md.) · 2015Article
- Identification of presumed pathogenic KRT3 and KRT12 gene mutations associated with Meesmann corneal dystrophy.Molecular vision · 2015Article
Corrections and comments
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Authors and funding
8 authors at 1 institution in 1 country.
Funding
Abstract
purposeTo identify an allele-specific short interfering RNA (siRNA), against the common KRT12 mutation Arg135Thr in Meesmann epithelial corneal dystrophy (MECD) as a personalized approach to treatment.
methodssiRNAs against the K12 Arg135Thr mutation were evaluated using a dual luciferase reporter gene assay and the most potent and specific siRNAs were further screened by Western blot. Off-target effects on related keratins were assessed and immunological stimulation of TLR3 was evaluated by RT-PCR. A modified 5' rapid amplification of cDNA ends method was used to confirm siRNA-mediated mutant knockdown. Allele discrimination was confirmed by quantitative infrared immunoblotting.
resultsThe lead siRNA, with an IC(50) of thirty picomolar, showed no keratin off-target effects or activation of TLR3 in the concentration ranges tested. We confirmed siRNA-mediated knockdown by the presence of K12 mRNA fragments cleaved at the predicted site. A dual tag infrared immunoblot showed knockdown to be allele-specific, with 70% to 80% silencing of the mutant protein.
conclusionsA potent allele-specific siRNA against the K12 Arg135Thr mutation was identified. In combination with efficient eyedrop formulation delivery, this would represent a personalized medicine approach, aimed at preventing the pathology associated with MECD and other ocular surface pathologies with dominant-negative or gain-of-function pathomechanisms.
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