ArticleMolecular therapy. Nucleic acids2019
Efficient Knockdown and Lack of Passenger Strand Activity by Dicer-Independent shRNAs Expressed from Pol II-Driven MicroRNA Scaffolds.
Article in Molecular therapy. Nucleic acids, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed.
- AAV-mediated multiple gene therapy combining VEGFA-targeting miR-agshRNAs and PEDF for the suppression of choroidal neovascularization.Molecular therapy. Nucleic acids · 2026Article
- Molecular Therapeutics for Diabetic Kidney Disease: An Update.International journal of molecular sciences · 2024Review
- Subretinal AAV delivery of RNAi-therapeutics targetingMolecular therapy. Methods & clinical development · 2024Article
- 25 years of maturation: A systematic review of RNAi in the clinic.Molecular therapy. Nucleic acids · 2023Review
- Terminal bridging of siRNA duplex at the ribose 2' position controls strand bias and target sequence preference.Molecular therapy. Nucleic acids · 2023Article
- A Circular RNA Expressed from the FAT3 Locus Regulates Neural Development.Molecular neurobiology · 2023Article
- Article
- miRNA-Mediated Knockdown of ATXN3 Alleviates Molecular Disease Hallmarks in a Mouse Model for Spinocerebellar Ataxia Type 3.Nucleic acid therapeutics · 2022Article
- Article
- Gene Therapy Intervention in Neovascular Eye Disease: A Recent Update.Molecular therapy : the journal of the American Society of Gene Therapy · 2020Review
- Short Hairpin RNAs for Strand-Specific Small Interfering RNA Production.Frontiers in bioengineering and biotechnology · 2020Article
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Authors and funding
6 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The expression of short hairpin RNAs (shRNAs) may result in unwanted activity from the co-processed passenger strand. Recent studies have shown that shortening the stem of conventional shRNAs abolishes passenger strand release. These Dicer-independent shRNAs, expressed from RNA polymerase III (Pol III) promoters, rely on Ago2 processing in resemblance to miR-451. Using strand-specific reporters, we tested two designs, and our results support the loss of passenger strand activity. We demonstrate that artificial primary microRNA (pri-miRNA) transcripts, expressed from Pol II promoters, can potently silence a gene of choice. Among six different scaffolds tested, miR-324 and miR-451 were readily re-targeted to direct efficient knockdown from either a CMV or a U1 snRNA promoter. Importantly, the miR-shRNAs have no passenger strand activity and remain active in Dicer-knockout cells. Our vectors are straightforward to design, as we replace the pre-miR-324 or -451 sequences with a Dicer-independent shRNA mimicking miR-451 with unpaired A-C nucleotides at the base. The use of Pol II promoters allows for controlled expression, while the inclusion of pri-miRNA sequences likely requires Drosha processing and, as such, mimics microRNA biogenesis. Since this improved and tunable system bypasses the requirement for Dicer activity and abolishes passenger strand activity completely, it will likely prove favorable in both research and therapeutic applications in terms of versatility and enhanced safety.
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