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      The Risks of miRNA Therapeutics: In a Drug Target Perspective

      review-article
      1 , 2 , 3 , 1 , 1
      Drug Design, Development and Therapy
      Dove
      RNAi, miRNA, siRNA, therapeutics

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          Abstract

          RNAi therapeutics have been growing. Patisiran and givosiran, two siRNA-based drugs, were approved by the Food and Drug Administration in 2018 and 2019, respectively. However, there is rare news on the advance of miRNA drugs (another therapeutic similar to siRNA drug). Here we report the existing obstacles of miRNA therapeutics by analyses for resources available in a drug target perspective, despite being appreciated when it began. Only 10 obtainable miRNA drugs have been in clinical trials with none undergoing phase III, while over 60 siRNA drugs are in complete clinical trial progression including two approvals. We mechanically compared the two types of drug and found that their major distinction lay in the huge discrepancy of the target number of two RNA molecules, which was caused by different complementary ratios. One miRNA generally targets tens and even hundreds of genes. We named it “too many targets for miRNA effect” (TMTME). Further, two adverse events from the discontinuation of two miRNA therapeutics were exactly answered by TMTME. In summary, TMTME is inevitable because of the special complementary approach between miRNA and its target. It means that miRNA therapeutics would trigger a series of unknown and unpreventable consequences, which makes it a considerable alternative for application.

          Most cited references90

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          Natural RNA circles function as efficient microRNA sponges.

          MicroRNAs (miRNAs) are important post-transcriptional regulators of gene expression that act by direct base pairing to target sites within untranslated regions of messenger RNAs. Recently, miRNA activity has been shown to be affected by the presence of miRNA sponge transcripts, the so-called competing endogenous RNA in humans and target mimicry in plants. We previously identified a highly expressed circular RNA (circRNA) in human and mouse brain. Here we show that this circRNA acts as a miR-7 sponge; we term this circular transcript ciRS-7 (circular RNA sponge for miR-7). ciRS-7 contains more than 70 selectively conserved miRNA target sites, and it is highly and widely associated with Argonaute (AGO) proteins in a miR-7-dependent manner. Although the circRNA is completely resistant to miRNA-mediated target destabilization, it strongly suppresses miR-7 activity, resulting in increased levels of miR-7 targets. In the mouse brain, we observe overlapping co-expression of ciRS-7 and miR-7, particularly in neocortical and hippocampal neurons, suggesting a high degree of endogenous interaction. We further show that the testis-specific circRNA, sex-determining region Y (Sry), serves as a miR-138 sponge, suggesting that miRNA sponge effects achieved by circRNA formation are a general phenomenon. This study serves as the first, to our knowledge, functional analysis of a naturally expressed circRNA.
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            MicroRNA therapeutics: towards a new era for the management of cancer and other diseases

            MicroRNAs (miRNAs) are small non-coding RNAs that can modulate mRNA expression. Insights into the roles of miRNAs in development and disease have led to the development of new therapeutic approaches that are based on miRNA mimics or agents that inhibit their functions (antimiRs), and the first such approaches have entered the clinic. This Review discusses the role of different miRNAs in cancer and other diseases, and provides an overview of current miRNA therapeutics in the clinic.
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              KOBAS 2.0: a web server for annotation and identification of enriched pathways and diseases

              High-throughput experimental technologies often identify dozens to hundreds of genes related to, or changed in, a biological or pathological process. From these genes one wants to identify biological pathways that may be involved and diseases that may be implicated. Here, we report a web server, KOBAS 2.0, which annotates an input set of genes with putative pathways and disease relationships based on mapping to genes with known annotations. It allows for both ID mapping and cross-species sequence similarity mapping. It then performs statistical tests to identify statistically significantly enriched pathways and diseases. KOBAS 2.0 incorporates knowledge across 1327 species from 5 pathway databases (KEGG PATHWAY, PID, BioCyc, Reactome and Panther) and 5 human disease databases (OMIM, KEGG DISEASE, FunDO, GAD and NHGRI GWAS Catalog). KOBAS 2.0 can be accessed at http://kobas.cbi.pku.edu.cn.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                dddt
                dddt
                Drug Design, Development and Therapy
                Dove
                1177-8881
                22 February 2021
                2021
                : 15
                : 721-733
                Affiliations
                [1 ]Jiangxi Institute of Respiratory Disease, The First Affiliated Hospital of Nanchang University , Nanchang, 330006, People’s Republic of China
                [2 ]College of Pharmaceutical Sciences, Zhejiang University , Hangzhou, 310058, People’s Republic of China
                [3 ]Department of Burn, The First Affiliated Hospital of Nanchang University , Nanchang, 330006, People’s Republic of China
                Author notes
                Correspondence: Tianyu Han Email hantianyu87@163.com
                Article
                288859
                10.2147/DDDT.S288859
                7910153
                33654378
                d5b293e0-f431-4a5f-801a-4e4fd457bc8e
                © 2021 Zhang et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                History
                : 02 November 2020
                : 12 December 2020
                Page count
                Figures: 5, Tables: 2, References: 90, Pages: 13
                Categories
                Review

                Pharmacology & Pharmaceutical medicine
                rnai,mirna,sirna,therapeutics
                Pharmacology & Pharmaceutical medicine
                rnai, mirna, sirna, therapeutics

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