ArticleProceedings of the National Academy of Sciences of the United States of America2015
Alleviation of off-target effects from vector-encoded shRNAs via codelivered RNA decoys.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
26 citing papers in PubMed.
- Construction and Characterization of Paired Patient-Derived Cell Models for Solitary Fibrous Tumors (SFTs).Cancers · 2026Article
- Silencing hepatic PCSK9 via novel chimeric AAV8 mitigates the progression of atherosclerosis by inhibiting inflammation in ApoEMolecular therapy. Methods & clinical development · 2025Article
- CDC42 deficiency leads to endometrial stromal cell senescence in recurrent implantation failure.Human reproduction (Oxford, England) · 2024Article
- CCL2 signaling promotes skeletal muscle wasting in non-tumor and breast tumor models.Disease models & mechanisms · 2024Article
- Advances in designing Adeno-associated viral vectors for development of anti-HBV gene therapeutics.Virology journal · 2021Review
- Mapping regulators of cell fate determination: Approaches and challenges.APL bioengineering · 2020Review
- Review
- Effective and Accurate Gene Silencing by a Recombinant AAV-Compatible MicroRNA Scaffold.Molecular therapy : the journal of the American Society of Gene Therapy · 2020Article
- Gene knockdown in malaria parasites via non-canonical RNAi.Nucleic acids research · 2020Article
- Advances in targeted degradation of endogenous proteins.Cellular and molecular life sciences : CMLS · 2019Review
- Efficient Knockdown and Lack of Passenger Strand Activity by Dicer-Independent shRNAs Expressed from Pol II-Driven MicroRNA Scaffolds.Molecular therapy. Nucleic acids · 2019Article
- Enhanced Tailored MicroRNA Sponge Activity of RNA Pol II-Transcribed TuD Hairpins Relative to Ectopically Expressed ciRS7-Derived circRNAs.Molecular therapy. Nucleic acids · 2018Article
- AAVvector-mediated in vivo reprogramming into pluripotency.Nature communications · 2018Article
- miRNA122a regulation of gene therapy vectors targeting hepatocellular cancer stem cells.Oncotarget · 2018Article
- RNA accessibility impacts potency of Tough Decoy microRNA inhibitors.RNA biology · 2018Article
- ABCB1 Mediates Cabazitaxel-Docetaxel Cross-Resistance in Advanced Prostate Cancer.Molecular cancer therapeutics · 2017Article
- Improved microRNA suppression by WPRE-linked tough decoy microRNA sponges.RNA (New York, N.Y.) · 2017Article
- Future of rAAV Gene Therapy: Platform for RNAi, Gene Editing, and Beyond.Human gene therapy · 2017Article
- TALEN/CRISPR-mediated engineering of a promoterless anti-viral RNAi hairpin into an endogenous miRNA locus.Nucleic acids research · 2017Article
- RNAi mechanisms in Huntington's disease therapy: siRNA versus shRNA.Translational neurodegeneration · 2017Review
Corrections and comments
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Authors and funding
5 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Exogenous RNAi triggers such as shRNAs ideally exert their activities exclusively via the antisense strand that binds and silences designated target mRNAs. However, in principle, the sense strand also possesses silencing capacity that may contribute to adverse RNAi side effects including off-target gene regulation. Here, we address this concern with a novel strategy that reduces sense strand activity of vector-encoded shRNAs via codelivery of inhibitory tough decoy (TuD) RNAs. Using various shRNAs for proof of concept, we validate that coexpression of TuDs can sequester and inactivate shRNA sense strands in human cells selectively without affecting desired antisense activities from the same shRNAs. Moreover, we show how coexpressed TuDs can alleviate shRNA-mediated perturbation of global gene expression by specifically de-repressing off-target transcripts carrying seed matches to the shRNA sense strand. Our combination of shRNA and TuD in a single bicistronic gene transfer vector derived from Adeno-associated virus (AAV) enables a wide range of applications, including gene therapies. To this end, we engineered our constructs in a modular fashion and identified simple hairpin design rules permitting adaptation to preexisting or new shRNAs. Finally, we demonstrate the power of our vectors for combinatorial RNAi strategies by showing robust suppression of hepatitis C virus (HCV) with an AAV expressing a bifunctional TuD against an anti-HCV shRNA sense strand and an HCV-related cellular miRNA. The data and tools reported here represent an important step toward the next generation of RNAi triggers with increased specificity and thus ultimately safety in humans.
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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.