AntimiR treatment corrects myotonic dystrophy primary cell defects across several CTG repeat expansions with a dual mechanism of action

This study evaluated therapeutic antimiRs in primary myoblasts from patients with myotonic dystrophy type 1 (DM1). DM1 results from unstable CTG repeat expansions in the DMPK gene, leading to variable clinical manifestations by depleting muscleblind-like splicing regulator protein MBNL1. AntimiRs ta...

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Detalles Bibliográficos
Autores: Cerro-Herreros, E., Núñez-Manchón, Judit|||0000-0001-5154-1454, Naldaiz-Gastesi, N., Carrascosa-Sàez, M., García-Rey, A., Losilla, D.P., González-Martínez, I., Espinosa-Espinosa, J., Moreno, K., Poyatos-García, J., Vilchez, J.J., López de Munain, A., Suelves, Mònica|||0000-0001-7095-5804, Nogales, Gisela|||0000-0002-7414-212X, Llamusí, B., Artero, R.
Tipo de recurso: artículo
Fecha de publicación:2024
País:España
Institución:Universitat Autònoma de Barcelona
Repositorio:Dipòsit Digital de Documents de la UAB
Idioma:inglés
OAI Identifier:oai:ddd.uab.cat:310582
Acceso en línea:https://ddd.uab.cat/record/310582
https://dx.doi.org/urn:doi:10.1126/sciadv.adn6525
Access Level:acceso abierto
Palabra clave:Clinical manifestation
Dual mechanisms
Fusion indices
Genetic backgrounds
Mechanism of action
Myoblasts
Myotonic dystrophy
Myotubes
Pharmacological profiles
Primary cells
Antagomirs
Cells, Cultured
Gene Expression Regulation
Humans
MicroRNAs
Myotonic Dystrophy
Myotonin-Protein Kinase
RNA-Binding Proteins
Trinucleotide Repeat Expansion
Descripción
Sumario:This study evaluated therapeutic antimiRs in primary myoblasts from patients with myotonic dystrophy type 1 (DM1). DM1 results from unstable CTG repeat expansions in the DMPK gene, leading to variable clinical manifestations by depleting muscleblind-like splicing regulator protein MBNL1. AntimiRs targeting natural repressors miR-23b and miR-218 boost MBNL1 expression but must be optimized for a better pharmacological profile in humans. In untreated cells, miR-23b and miR-218 were up-regulated, which correlated with CTG repeat size, supporting that active MBNL1 protein repression synergizes with the sequestration by CUG expansions in DMPK. AntimiR treatment improved RNA toxicity readouts and corrected regulated exon inclusions and myoblast defects such as fusion index and myotube area across CTG expansions. Unexpectedly, the treatment also reduced DMPK transcripts and ribonuclear foci. A leading antimiR reversed 68% of dysregulated genes. This study highlights the potential of antimiRs to treat various DM1 forms across a range of repeat sizes and genetic backgrounds by mitigating MBNL1 sequestration and enhancing protein synthesis.

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