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 <i>DMPK</i> 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 <i>DMPK</i>. 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 <i>DMPK</i> 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.
Authors
- Gisela Nogales‐Gadea (ORCID: https://orcid.org/0000-0002-7414-212X)
- Mònica Suelves (ORCID: https://orcid.org/0000-0001-7095-5804)
- Neia Naldaiz‐Gastesi (ORCID: https://orcid.org/0000-0003-0901-8429)
- Javier Poyatos‐García (ORCID: https://orcid.org/0000-0003-3117-4743)
- Jorge Espinosa-Espinosa (ORCID: https://orcid.org/0000-0003-0098-5201)
- Judit Núñez‐Manchón (ORCID: https://orcid.org/0000-0001-5154-1454)
- Beatriz Llamusí (ORCID: https://orcid.org/0000-0002-2694-1293)
- Irene González-Martínez (ORCID: https://orcid.org/0000-0002-3507-5227)
- Kévin Moreno (ORCID: https://orcid.org/0009-0006-1089-2227)
- Estefanía Cerro-Herreros (ORCID: https://orcid.org/0000-0003-3247-5900)
- Juan J. Vílchez (ORCID: https://orcid.org/0000-0002-0532-2872)
- Rubén Artero (ORCID: https://orcid.org/0000-0003-1596-047X)
- Andrea García-Rey
- Marc Carrascosa-Sàez (ORCID: https://orcid.org/0000-0002-5477-8323)
- Diego Piqueras Losilla (ORCID: https://orcid.org/0009-0003-2667-234X)
- Adolfo López de Munaín
Institutions
- Universitat de València (ES)
- University of the Basque Country (ES)
- Parc Científic de la Universitat de València (ES)
- Instituto de Salud Carlos III (ES)
- Biogipuzkoa Health Research Institute (ES)
- Centre for Biomedical Network Research on Rare Diseases (ES)
- Leitat Technological Center (ES)
- Osakidetza (ES)
- Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol (ES)
- Instituto de Investigación Sanitaria La Fe (ES)
- Universidad Internacional SEK (EC)
- Menéndez Pelayo International University (ES)
Publication Details
- Journal
- Science Advances
- Published
- 2024-10-09
- DOI
- https://doi.org/10.1126/sciadv.adn6525
- Citations
- 8
- Primary Topic
- Genetic Neurodegenerative Diseases
- Type
- article
- Field-Weighted Citation Impact
- 2.15
Funders
- Generalitat Valenciana
- Ministerio de Ciencia e Innovación
- EIT Health