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      Current prospects for RNA interference-based therapies

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          Key Points

          • RNA interference (RNAi) is a powerful approach for reducing expression of endogenously expressed proteins for biological applications, or targeting the expression of pathological proteins for therapy.

          • Several delivery methods are available to achieve RNAi in ex vivo and in vivo settings for therapeutic results.

          • The development of RNAi-based therapeutics has advanced sufficiently to allow human clinical trials to begin.

          • Here we outline the broad range of cell-, tissue- and disease-specific approaches under investigation for RNAi therapeutics.

          • The barriers posed by certain cells and tissues are described, as are issues with off-target silencing.

          Abstract

          RNA interference can elicit specific gene silencing and so holds great potential for treating infectious or genetic diseases. Several small-RNA-based therapies have now reached clinical trials, but further work is still needed to improve delivery and efficacy.

          Abstract

          RNA interference (RNAi) is a powerful approach for reducing expression of endogenously expressed proteins. It is widely used for biological applications and is being harnessed to silence mRNAs encoding pathogenic proteins for therapy. Various methods — including delivering RNA oligonucleotides and expressing RNAi triggers from viral vectors — have been developed for successful RNAi in cell culture and in vivo. Recently, RNAi-based gene silencing approaches have been demonstrated in humans, and ongoing clinical trials hold promise for treating fatal disorders or providing alternatives to traditional small molecule therapies. Here we describe the broad range of approaches to achieve targeted gene silencing for therapy, discuss important considerations when developing RNAi triggers for use in humans, and review the current status of clinical trials.

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          Most cited references 121

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          Prediction of mammalian microRNA targets.

          MicroRNAs (miRNAs) can play important gene regulatory roles in nematodes, insects, and plants by basepairing to mRNAs to specify posttranscriptional repression of these messages. However, the mRNAs regulated by vertebrate miRNAs are all unknown. Here we predict more than 400 regulatory target genes for the conserved vertebrate miRNAs by identifying mRNAs with conserved pairing to the 5' region of the miRNA and evaluating the number and quality of these complementary sites. Rigorous tests using shuffled miRNA controls supported a majority of these predictions, with the fraction of false positives estimated at 31% for targets identified in human, mouse, and rat and 22% for targets identified in pufferfish as well as mammals. Eleven predicted targets (out of 15 tested) were supported experimentally using a HeLa cell reporter system. 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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            Nuclear export of microRNA precursors.

            MicroRNAs (miRNAs), which function as regulators of gene expression in eukaryotes, are processed from larger transcripts by sequential action of nuclear and cytoplasmic ribonuclease III-like endonucleases. We show that Exportin-5 (Exp5) mediates efficient nuclear export of short miRNA precursors (pre-miRNAs) and that its depletion by RNA interference results in reduced miRNA levels. Exp5 binds correctly processed pre-miRNAs directly and specifically, in a Ran guanosine triphosphate-dependent manner, but interacts only weakly with extended pre-miRNAs that yield incorrect miRNAs when processed by Dicer in vitro. Thus, Exp5 is key to miRNA biogenesis and may help coordinate nuclear and cytoplasmic processing steps.
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              Small silencing RNAs: an expanding universe.

              Since the discovery in 1993 of the first small silencing RNA, a dizzying number of small RNA classes have been identified, including microRNAs (miRNAs), small interfering RNAs (siRNAs) and Piwi-interacting RNAs (piRNAs). These classes differ in their biogenesis, their modes of target regulation and in the biological pathways they regulate. There is a growing realization that, despite their differences, these distinct small RNA pathways are interconnected, and that small RNA pathways compete and collaborate as they regulate genes and protect the genome from external and internal threats.
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                Author and article information

                Contributors
                beverly-davidson@uiowa.edu
                Journal
                Nat Rev Genet
                Nat. Rev. Genet
                Nature Reviews. Genetics
                Nature Publishing Group UK (London )
                1471-0056
                1471-0064
                18 April 2011
                2011
                : 12
                : 5
                : 329-340
                Affiliations
                [1 ]GRID grid.214572.7, ISNI 0000 0004 1936 8294, Departments of Internal Medicine, , Roy J. and Lucille A. Carver College of Medicine, University of Iowa, ; Iowa City, 52242 Iowa USA
                [2 ]GRID grid.214572.7, ISNI 0000 0004 1936 8294, Departments of Neurology, , Roy J. and Lucille A. Carver College of Medicine, University of Iowa, ; Iowa City, 52242 Iowa USA
                [3 ]GRID grid.214572.7, ISNI 0000 0004 1936 8294, Departments of Physiology & Biophysics, , Roy J. and Lucille A. Carver College of Medicine, University of Iowa, ; Iowa City, 52242 Iowa USA
                [4 ]GRID grid.214572.7, ISNI 0000 0004 1936 8294, Departments of Pediatrics, , Roy J. and Lucille A. Carver College of Medicine, University of Iowa, ; Iowa City, 52242 Iowa USA
                Article
                BFnrg2968
                10.1038/nrg2968
                7097665
                21499294
                © Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved. 2011

                This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.

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                © Springer Nature Limited 2011

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