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BlockmiR AONs as Site-Specific Therapeutic MBNL Modulation in Myotonic Dystrophy 2D and 3D Muscle Cells and HSA(LR) Mice

The symptoms of Myotonic Dystrophy Type 1 (DM1) are multi-systemic and life-threatening. The neuromuscular disorder is rooted in a non-coding CTG microsatellite expansion in the DM1 protein kinase (DMPK) gene that, upon transcription, physically sequesters the Muscleblind-like (MBNL) family of splic...

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Autores principales: Overby, Sarah J., Cerro-Herreros, Estefanía, Espinosa-Espinosa, Jorge, González-Martínez, Irene, Moreno, Nerea, Fernández-Costa, Juan M., Balaguer-Trias, Jordina, Ramón-Azcón, Javier, Pérez-Alonso, Manuel, Møller, Thorleif, Llamusí, Beatriz, Artero, Rubén
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10141141/
https://www.ncbi.nlm.nih.gov/pubmed/37111604
http://dx.doi.org/10.3390/pharmaceutics15041118
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author Overby, Sarah J.
Cerro-Herreros, Estefanía
Espinosa-Espinosa, Jorge
González-Martínez, Irene
Moreno, Nerea
Fernández-Costa, Juan M.
Balaguer-Trias, Jordina
Ramón-Azcón, Javier
Pérez-Alonso, Manuel
Møller, Thorleif
Llamusí, Beatriz
Artero, Rubén
author_facet Overby, Sarah J.
Cerro-Herreros, Estefanía
Espinosa-Espinosa, Jorge
González-Martínez, Irene
Moreno, Nerea
Fernández-Costa, Juan M.
Balaguer-Trias, Jordina
Ramón-Azcón, Javier
Pérez-Alonso, Manuel
Møller, Thorleif
Llamusí, Beatriz
Artero, Rubén
author_sort Overby, Sarah J.
collection PubMed
description The symptoms of Myotonic Dystrophy Type 1 (DM1) are multi-systemic and life-threatening. The neuromuscular disorder is rooted in a non-coding CTG microsatellite expansion in the DM1 protein kinase (DMPK) gene that, upon transcription, physically sequesters the Muscleblind-like (MBNL) family of splicing regulator proteins. The high-affinity binding occurring between the proteins and the repetitions disallow MBNL proteins from performing their post-transcriptional splicing regulation leading to downstream molecular effects directly related to disease symptoms such as myotonia and muscle weakness. In this study, we build on previously demonstrated evidence showing that the silencing of miRNA-23b and miRNA-218 can increase MBNL1 protein in DM1 cells and mice. Here, we use blockmiR antisense technology in DM1 muscle cells, 3D mouse-derived muscle tissue, and in vivo mice to block the binding sites of these microRNAs in order to increase MBNL translation into protein without binding to microRNAs. The blockmiRs show therapeutic effects with the rescue of mis-splicing, MBNL subcellular localization, and highly specific transcriptomic expression. The blockmiRs are well tolerated in 3D mouse skeletal tissue inducing no immune response. In vivo, a candidate blockmiR also increases Mbnl1/2 protein and rescues grip strength, splicing, and histological phenotypes.
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spelling pubmed-101411412023-04-29 BlockmiR AONs as Site-Specific Therapeutic MBNL Modulation in Myotonic Dystrophy 2D and 3D Muscle Cells and HSA(LR) Mice Overby, Sarah J. Cerro-Herreros, Estefanía Espinosa-Espinosa, Jorge González-Martínez, Irene Moreno, Nerea Fernández-Costa, Juan M. Balaguer-Trias, Jordina Ramón-Azcón, Javier Pérez-Alonso, Manuel Møller, Thorleif Llamusí, Beatriz Artero, Rubén Pharmaceutics Article The symptoms of Myotonic Dystrophy Type 1 (DM1) are multi-systemic and life-threatening. The neuromuscular disorder is rooted in a non-coding CTG microsatellite expansion in the DM1 protein kinase (DMPK) gene that, upon transcription, physically sequesters the Muscleblind-like (MBNL) family of splicing regulator proteins. The high-affinity binding occurring between the proteins and the repetitions disallow MBNL proteins from performing their post-transcriptional splicing regulation leading to downstream molecular effects directly related to disease symptoms such as myotonia and muscle weakness. In this study, we build on previously demonstrated evidence showing that the silencing of miRNA-23b and miRNA-218 can increase MBNL1 protein in DM1 cells and mice. Here, we use blockmiR antisense technology in DM1 muscle cells, 3D mouse-derived muscle tissue, and in vivo mice to block the binding sites of these microRNAs in order to increase MBNL translation into protein without binding to microRNAs. The blockmiRs show therapeutic effects with the rescue of mis-splicing, MBNL subcellular localization, and highly specific transcriptomic expression. The blockmiRs are well tolerated in 3D mouse skeletal tissue inducing no immune response. In vivo, a candidate blockmiR also increases Mbnl1/2 protein and rescues grip strength, splicing, and histological phenotypes. MDPI 2023-03-31 /pmc/articles/PMC10141141/ /pubmed/37111604 http://dx.doi.org/10.3390/pharmaceutics15041118 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Overby, Sarah J.
Cerro-Herreros, Estefanía
Espinosa-Espinosa, Jorge
González-Martínez, Irene
Moreno, Nerea
Fernández-Costa, Juan M.
Balaguer-Trias, Jordina
Ramón-Azcón, Javier
Pérez-Alonso, Manuel
Møller, Thorleif
Llamusí, Beatriz
Artero, Rubén
BlockmiR AONs as Site-Specific Therapeutic MBNL Modulation in Myotonic Dystrophy 2D and 3D Muscle Cells and HSA(LR) Mice
title BlockmiR AONs as Site-Specific Therapeutic MBNL Modulation in Myotonic Dystrophy 2D and 3D Muscle Cells and HSA(LR) Mice
title_full BlockmiR AONs as Site-Specific Therapeutic MBNL Modulation in Myotonic Dystrophy 2D and 3D Muscle Cells and HSA(LR) Mice
title_fullStr BlockmiR AONs as Site-Specific Therapeutic MBNL Modulation in Myotonic Dystrophy 2D and 3D Muscle Cells and HSA(LR) Mice
title_full_unstemmed BlockmiR AONs as Site-Specific Therapeutic MBNL Modulation in Myotonic Dystrophy 2D and 3D Muscle Cells and HSA(LR) Mice
title_short BlockmiR AONs as Site-Specific Therapeutic MBNL Modulation in Myotonic Dystrophy 2D and 3D Muscle Cells and HSA(LR) Mice
title_sort blockmir aons as site-specific therapeutic mbnl modulation in myotonic dystrophy 2d and 3d muscle cells and hsa(lr) mice
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10141141/
https://www.ncbi.nlm.nih.gov/pubmed/37111604
http://dx.doi.org/10.3390/pharmaceutics15041118
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