BlockmiR AONs as Site-Specific Therapeutic MBNL Modulation in Myotonic Dystrophy 2D and 3D Muscle Cells and HSA[sup.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...

Full description

Saved in:
Bibliographic Details
Published in:Pharmaceutics 2023-04, Vol.15 (4)
Main Authors: 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
Format: Article
Language:English
Subjects:
Analysis
Care and treatment
Diagnosis
Genetic aspects
MicroRNA
Myotonic dystrophy
Phenotype
Protein kinases
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:1999-4923
1999-4923
DOI:10.3390/pharmaceutics15041118