CRISPR-mediated targeting of the LMNA c.745C>T pathogenic mutation enhances survival and cardiac function in congenital muscular dystrophy.

Gomez-Dominguez, DeborahEpifano, CarolinaHernández Martínez, IvánVilaplana-Marti, BorjaMartin, AlbertoAmarilla-Quintana, SandraCesar, Sergide Molina-Iracheta, AntonioSena-Esteves, MiguelSarquella-Brugada, GeorgiaPerez de Castro, Ignacio2026-01-122026-01-122025-12Gómez-Domínguez D, Epifano C, Hernández I, Vilaplana-Martí B, Martín A, Amarilla-Quintana S, Cesar S, de Molina-Iracheta A, Sena-Esteves M, Sarquella-Brugada G, Pérez de Castro I, CRISPR-mediated targeting of the LMNA c.745C>T pathogenic mutation enhances survival and cardiac function in congenital muscular dystrophy, Molecular Therapy Advances (2026), doi: https:// doi.org/10.1016/j.omta.2025.201653.3117-387Xhttps://hdl.handle.net/20.500.12105/27142LMNA-associated congenital muscular dystrophy is a currently incurable rare genetic disorder characterized by early-onset muscle weakness, dilated cardiomyopathy and respiratory failure, resulting from mutations in the LMNA gene. In this study, we assessed the potential of a CRISPR-mediated strategy to eliminate the mutant allele Lmna c.745C>T, p.R249W using a mutation specific guide (sg745T). Results from R249W-mutation-carrying cellular models showed specific activity of the Cas9/sg745T complex towards the mutant allele. This property varied depending on the concentration of CRISPR components, with a loss of specificity observed with increased dosage. We tested this strategy in vivo using adeno-associated virus delivery in LmnaR249W mice. Despite being associated with a modest CRISPR activity, this therapeutic approach led to a 10% (non-significant) increase in the survival of R249W homozygous mice. Interestingly, a comparable CRISPR activity significantly ameliorated the cardiac pathology observed in Lmna+/R249W animals, resulting in a significant 24.3% extension of their median survival. These results represent the first therapeutic validation of a CRISPR/Cas9-mediated gene editing strategy for the treatment of LMNA-associated congenital muscular dystrophy.engPhttp://creativecommons.org/licenses/by/4.0/LMNAL-CMDLaminopathiesCRISPR/Cas9Gene therapyRare diseaseCRISPR-mediated targeting of the LMNA c.745C>T pathogenic mutation enhances survival and cardiac function in congenital muscular dystrophy.Attribution 4.0 International10.1016/j.omta.2025.201653Molecular Therapy Advancesopen access