AntimiR treatment corrects myotonic dystrophy primary cell defects across several CTG repeat expansions with a dual mechanism of action
Cerro-Herreros, E. (Parque Científico de la Universidad de Valencia)
Núñez-Manchón, Judit (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol)
Naldaiz-Gastesi, N. (Instituto de Salud Carlos III)
Carrascosa-Sàez, M. (Parque Científico de la Universidad de Valencia)
García-Rey, A. (INCLIVA Institut d'Investigació Sanitària)
Losilla, D.P. (Parque Científico de la Universidad de Valencia)
González-Martínez, I. (Instituto de Salud Carlos III)
Espinosa-Espinosa, J. (Universidad Particular Internacional SEK (UISEK))
Moreno, K. (Parque Científico de la Universidad de Valencia)
Poyatos-García, J. (Hospital Universitari i Politècnic La Fe (València))
Vilchez, J.J. (Hospital Universitari i Politècnic La Fe (València))
López de Munain, A. (Universidad del País Vasco)
Suelves, Mònica (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol)
Nogales, Gisela (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol)
Llamusí, B. (Parque Científico de la Universidad de Valencia)
Artero, R. (Instituto de Salud Carlos III)
Universitat Autònoma de Barcelona

Date:	2024
Abstract:	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.
Grants:	Instituto de Salud Carlos III PI22/00104 Agencia Estatal de Investigación PID2020-118730RB-I00
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	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
Published in:	Science advances, Vol. 10 Núm. 41 (november 2024) , p. eadn6525, ISSN 2375-2548

DOI: 10.1126/sciadv.adn6525
PMID: 39383229

17 p, 9.3 MB

The record appears in these collections:
Research literature > UAB research groups literature > Research Centres and Groups (research output) > Health sciences and biosciences > Institut d'Investigació en Ciencies de la Salut Germans Trias i Pujol (IGTP)
Articles > Research articles
Articles > Published articles