miR-23b and miR-218 silencing increase Muscleblind-like expression and alleviate myotonic dystrophy phenotypes in mammalian models

Estefania Cerro-Herreros, Maria Sabater-Arcis, Juan M. Fernandez-Costa, Nerea Moreno, Manuel Perez-Alonso, Beatriz Llamusi () and Ruben Artero ()
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Estefania Cerro-Herreros: University of Valencia
Maria Sabater-Arcis: University of Valencia
Juan M. Fernandez-Costa: University of Valencia
Nerea Moreno: University of Valencia
Manuel Perez-Alonso: University of Valencia
Beatriz Llamusi: University of Valencia
Ruben Artero: University of Valencia

Nature Communications, 2018, vol. 9, issue 1, 1-13

Abstract: Abstract Functional depletion of the alternative splicing factors Muscleblind-like (MBNL 1 and 2) is at the basis of the neuromuscular disease myotonic dystrophy type 1 (DM1). We previously showed the efficacy of miRNA downregulation in Drosophila DM1 model. Here, we screen for miRNAs that regulate MBNL1 and MBNL2 in HeLa cells. We thus identify miR-23b and miR-218, and confirm that they downregulate MBNL proteins in this cell line. Antagonists of miR-23b and miR-218 miRNAs enhance MBNL protein levels and rescue pathogenic missplicing events in DM1 myoblasts. Systemic delivery of these “antagomiRs” similarly boost MBNL expression and improve DM1-like phenotypes, including splicing alterations, histopathology, and myotonia in the HSALR DM1 model mice. These mammalian data provide evidence for therapeutic blocking of the miRNAs that control Muscleblind-like protein expression in myotonic dystrophy.

Date: 2018
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DOI: 10.1038/s41467-018-04892-4

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