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MicroRNA-9 downregulates the ANO1 chloride channel and contributes to cystic fibrosis lung pathology

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      Abstract

      Cystic fibrosis results from reduced cystic fibrosis transmembrane conductance regulator protein activity leading to defective epithelial ion transport. Ca 2+-activated Cl channels mediate physiological functions independently of cystic fibrosis transmembrane conductance regulator. Anoctamin 1 (ANO1/TMEM16A) was identified as the major Ca 2+-activated Cl channel in airway epithelial cells, and we recently demonstrated that downregulation of the anoctamin 1 channel in cystic fibrosis patients contributes to disease severity via an unknown mechanism. Here we show that microRNA-9 (miR-9) contributes to cystic fibrosis and downregulates anoctamin 1 by directly targeting its 3′UTR. We present a potential therapy based on blockage of miR-9 binding to the 3′UTR by using a microRNA target site blocker to increase anoctamin 1 activity and thus compensate for the cystic fibrosis transmembrane conductance regulator deficiency. The target site blocker is tested in in vitro and in mouse models of cystic fibrosis, and could be considered as an alternative strategy to treat cystic fibrosis.

      Abstract

      Downregulation of the anoctamin 1 calcium channel in airway epithelial cells contributes to pathology in cystic fibrosis. Here the authors show that microRNA-9 targets anoctamin 1 and that inhibiting this interaction improves mucus dynamics in mouse models.

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      Most cited references 40

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      Treatment of HCV infection by targeting microRNA.

      The stability and propagation of hepatitis C virus (HCV) is dependent on a functional interaction between the HCV genome and liver-expressed microRNA-122 (miR-122). Miravirsen is a locked nucleic acid-modified DNA phosphorothioate antisense oligonucleotide that sequesters mature miR-122 in a highly stable heteroduplex, thereby inhibiting its function. In this phase 2a study at seven international sites, we evaluated the safety and efficacy of miravirsen in 36 patients with chronic HCV genotype 1 infection. The patients were randomly assigned to receive five weekly subcutaneous injections of miravirsen at doses of 3 mg, 5 mg, or 7 mg per kilogram of body weight or placebo over a 29-day period. They were followed until 18 weeks after randomization. Miravirsen resulted in a dose-dependent reduction in HCV RNA levels that endured beyond the end of active therapy. In the miravirsen groups, the mean maximum reduction in HCV RNA level (log10 IU per milliliter) from baseline was 1.2 (P=0.01) for patients receiving 3 mg per kilogram, 2.9 (P=0.003) for those receiving 5 mg per kilogram, and 3.0 (P=0.002) for those receiving 7 mg per kilogram, as compared with a reduction of 0.4 in the placebo group. During 14 weeks of follow-up after treatment, HCV RNA was not detected in one patient in the 5-mg group and in four patients in the 7-mg group. We observed no dose-limiting adverse events and no escape mutations in the miR-122 binding sites of the HCV genome. The use of miravirsen in patients with chronic HCV genotype 1 infection showed prolonged dose-dependent reductions in HCV RNA levels without evidence of viral resistance. (Funded by Santaris Pharma; ClinicalTrials.gov number, NCT01200420.).
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        Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA

         Riordan,  J Rommens,  B Kerem (1989)
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          TMEM16A confers receptor-activated calcium-dependent chloride conductance.

          Calcium (Ca(2+))-activated chloride channels are fundamental mediators in numerous physiological processes including transepithelial secretion, cardiac and neuronal excitation, sensory transduction, smooth muscle contraction and fertilization. Despite their physiological importance, their molecular identity has remained largely unknown. Here we show that transmembrane protein 16A (TMEM16A, which we also call anoctamin 1 (ANO1)) is a bona fide Ca(2+)-activated chloride channel that is activated by intracellular Ca(2+) and Ca(2+)-mobilizing stimuli. With eight putative transmembrane domains and no apparent similarity to previously characterized channels, ANO1 defines a new family of ionic channels. The biophysical properties as well as the pharmacological profile of ANO1 are in full agreement with native Ca(2+)-activated chloride currents. ANO1 is expressed in various secretory epithelia, the retina and sensory neurons. Furthermore, knockdown of mouse Ano1 markedly reduced native Ca(2+)-activated chloride currents as well as saliva production in mice. We conclude that ANO1 is a candidate Ca(2+)-activated chloride channel that mediates receptor-activated chloride currents in diverse physiological processes.
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            Author and article information

            Affiliations
            [1 ]ISNI 0000 0001 1955 3500, GRID grid.5805.8, Centre de Recherche Saint Antoine (CRSA), INSERM, , Sorbonne Universités, UPMC Univ Paris 06, ; F75012 Paris, France
            [2 ]ISNI 0000 0004 1937 0618, GRID grid.11667.37, INSERM UMR-S 903, , University of Reims Champagne-Ardenne, ; 51100 Reims, France
            [3 ]ISNI 0000 0001 2323 0229, GRID grid.12832.3a, Université de Versailles Saint Quentin en Yvelines, UFR des Sciences de la Santé, ; 78180 Montigny-Le-Bretonneux, France
            [4 ]ISNI 0000 0004 1937 1098, GRID grid.413776.0, Paediatric Respiratory Department, , Hôpital Trousseau, AP-HP, ; 75012 Paris, France
            Contributors
            ORCID: http://orcid.org/0000-0003-1997-2400, olivier.tabary@inserm.fr
            Journal
            Nat Commun
            Nat Commun
            Nature Communications
            Nature Publishing Group UK (London )
            2041-1723
            27 September 2017
            27 September 2017
            2017
            : 8
            28955034
            5617894
            813
            10.1038/s41467-017-00813-z
            © The Author(s) 2017

            Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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