ArticleFASEB journal : official publication of the Federation of American Societies for Experimental Biology2012
Allele-specific siRNA knockdown as a personalized treatment strategy for vascular Ehlers-Danlos syndrome in human fibroblasts.
Article in FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 33 citations in OpenAlex.
- Allele-specific RNAi therapy corrects an extracellular matrix defect in Schuurs-Hoeijmakers syndrome.American journal of human genetics · 2025Article
- Current Evidence and Future Perspectives in the Medical Management of Vascular Ehlers-Danlos Syndrome: Focus on Vascular Prevention.Journal of clinical medicine · 2024Review
- The double whammy of ER-retention and dominant-negative effects in numerous autosomal dominant diseases: significance in disease mechanisms and therapy.Journal of biomedical science · 2024Review
- Patient-derived extracellular matrix demonstrates role of COL3A1 in blood vessel mechanics.Acta biomaterialia · 2023Article
- Case report: Characterization of a rare pathogenic variant associated with loss of COL3A1 expression in vascular Ehlers Danlos syndrome.Frontiers in cardiovascular medicine · 2022Article
- Case report: Mild phenotype of a patient with vascular Ehlers-Danlos syndrome andFrontiers in genetics · 2022Article
- Four decades in the making: Collagen III and mechanisms of vascular Ehlers Danlos Syndrome.Matrix biology plus · 2021Review
- The Ehlers-Danlos syndromes.Nature reviews. Disease primers · 2020Review
- Allele-specific silencing therapy for Dynamin 2-related dominant centronuclear myopathy.EMBO molecular medicine · 2018Article
- Allele-specific RNA interference rescues the long-QT syndrome phenotype in human-induced pluripotency stem cell cardiomyocytes.European heart journal · 2014Article
- siRNA-mediated Allele-specific Silencing of a COL6A3 Mutation in a Cellular Model of Dominant Ullrich Muscular Dystrophy.Molecular therapy. Nucleic acids · 2014Article
- Research progress in allele-specific expression and its regulatory mechanisms.Journal of applied genetics · 2013Review
- Disease-causing allele-specific silencing by RNA interference.Pharmaceuticals (Basel, Switzerland) · 2013Article
- Allele dependent silencing of collagen type I using small interfering RNAs targeting 3'UTR Indels - a novel therapeutic approach in osteogenesis imperfecta.International journal of medical sciences · 2013Article
Corrections and comments
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Authors and funding
7 authors at 3 institutions in 2 countries.
Funding
Abstract
The vascular type of the Ehlers-Danlos syndrome (vEDS) is caused by dominant-negative mutations in the procollagen type III (COL3A1) gene. Patients with this autosomal dominant disorder have a shortened life expectancy due to complications from ruptured vessels or hollow organs. We tested the effectiveness of allele-specific RNA interference (RNAi) to reduce the mutated phenotype in fibroblasts. Small-interfering RNAs (siRNAs) discriminating between wild-type and mutant COL3A1 allele were identified by a luciferase reporter gene assay and in primary fibroblasts from a normal donor and a patient with vEDS. The best discriminative siRNA with the mutation at position 10 resulted in >90% silencing of the mutant allele without affecting the wild-type allele. Transmission and immunogold electron microscopy of extracted extracellular matrices from untreated fibroblasts of the patient with vEDS revealed structurally abnormal fibrils. After siRNA treatment, collagen fibrils became similar to fibrils from fibroblasts of normal and COL3A1 haploinsufficient donors. In addition, it was shown that expression of mutated COL3A1 activates the unfolded protein response and that reduction of the amount of mutated protein by siRNA reduces cellular stress. Taken together, the results provide evidence that allele-specific siRNAs are able to reduce negative effects of mutated COL3A1 proteins. Thus, the application of allele-specific RNAi may be a promising direction for future personalized therapies to reduce the severity of vEDS.
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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.