Journal ArticleDOI
Recognizing and avoiding siRNA off-target effects for target identification and therapeutic application.
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TLDR
The types of off-target effects of siRNAs and methods to mitigate them are described to help enable effective application of this exciting technology.Abstract:
Small interfering RNAs (siRNAs) are widely used to study gene function owing to the ease with which they silence target genes, and there is considerable interest in their potential for therapeutic applications. In a remarkably short time since their discovery, siRNAs have entered human clinical trials in various disease areas. However, rapid acceptance of the use of siRNAs has been accompanied by recognition of several hurdles for the technology, including a lack of specificity. Off-target activity can complicate the interpretation of phenotypic effects in gene-silencing experiments and can potentially lead to unwanted toxicities. Here, we describe the types of off-target effects of siRNAs and methods to mitigate them, to help enable effective application of this exciting technology.read more
Citations
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Journal ArticleDOI
Rasa3 controls turnover of endothelial cell adhesion and vascular lumen integrity by a Rap1-dependent mechanism.
Patricia Molina-Ortiz,Tanguy Orban,Maud Martin,Audrey Habets,Franck Dequiedt,Stéphane Schurmans +5 more
TL;DR: Rasa3 is a critical regulator of Rap1 in endothelial cells which controls adhesions properties and vascular lumen integrity; its specific endothelial cell inactivation results in occluded blood vessels, hemorrhages and early embryonic death in mouse, mimicking thus the Rasa3-/- mouse phenotype.
Journal ArticleDOI
Cytoplasm-Responsive Delivery Systems for siRNA Using Cell-Penetrating Peptide Nanomicelles
TL;DR: DNA vaccination and delivery of siRNA into the cytoplasm using functional CPP-conjugated nanomicelles using these functional siRNA transfection efficiency complexes are described.
Journal ArticleDOI
Stacking up CRISPR against RNAi for therapeutic gene inhibition.
TL;DR: It is found that largely because of their broadly overlapping delivery constraints, while CRISPR presents formidable competition for DNA‐directed RNAi strategies, its impact on RNAi therapeutics triggered by synthetic oligonucleotides will likely be more moderate.
Journal ArticleDOI
Therapeutic RNA interference: A novel approach to the treatment of primary hyperoxaluria.
TL;DR: Nedosiran and lumasiran are discussed, which are both novel RNAi therapies for primary hyperoxaluria that selectively reduce hepatic expression of lactate dehydrogenase and glycolate oxidase respectively, reducing hepatic oxalate production and urinary oxalates levels.
Journal ArticleDOI
Modulation of intrinsic inhibitory checkpoints using nano-carriers to unleash NK cell activity.
Guy Biber,Batel Sabag,Anat Raiff,Aviad Ben-Shmuel,Abhishek Puthenveetil,Jennifer I. C. Benichou,Tammir Jubany,Moria Levy,Shiran Killner,Mira Barda-Saad +9 more
TL;DR: In this article, a non-viral lipid nanoparticle-based delivery system that encapsulates small interfering RNAs (siRNAs) to gene silence the key intrinsic inhibitory NK cell molecules, SHP-1, Cbl-b, and c-Cbl.
References
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Journal ArticleDOI
MicroRNAs: Target Recognition and Regulatory Functions
TL;DR: The current understanding of miRNA target recognition in animals is outlined and the widespread impact of miRNAs on both the expression and evolution of protein-coding genes is discussed.
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Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells
TL;DR: 21-nucleotide siRNA duplexes provide a new tool for studying gene function in mammalian cells and may eventually be used as gene-specific therapeutics.
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Prediction of Mammalian MicroRNA Targets
TL;DR: The predicted regulatory targets of mammalian miRNAs were enriched for genes involved in transcriptional regulation but also encompassed an unexpectedly broad range of other functions.
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The nuclear RNase III Drosha initiates microRNA processing
Yoontae Lee,Chiyoung Ahn,Jinju Han,Hyounjeong Choi,Jaekwang Kim,Jeongbin Yim,Junho Lee,Patrick Provost,Olof Rådmark,Sun-Young Kim,V. Narry Kim +10 more
TL;DR: The two RNase III proteins, Drosha and Dicer, may collaborate in the stepwise processing of miRNAs, and have key roles in miRNA-mediated gene regulation in processes such as development and differentiation.
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Microarray analysis shows that some microRNAs downregulate large numbers of target mRNAs
Lee P. Lim,Nelson C. Lau,Philip W. Garrett-engele,Andrew Grimson,Janell M. Schelter,John C. Castle,David P. Bartel,Peter S. Linsley,Jason M. Johnson +8 more
TL;DR: These results suggest that metazoan miRNAs can reduce the levels of many of their target transcripts, not just the amount of protein deriving from these transcripts, and seem to downregulate a far greater number of targets than previously appreciated.