Authors
Déborah Gómez-Domínguez, Carolina Epifano, Iván Hernández, Borja Vilaplana-Martí, Alberto Martín, Sandra Amarilla-Quintana, Sergi Cesar, Antonio de Molina-Iracheta, Miguel Sena-Esteves, Georgia Sarquella-Brugada, Ignacio Pérez de Castro
Published in
Molecular therapy. Advances. Volume 34. Issue 1. Pages 201653. Mar 12, 2026. Epub Dec 26, 2025.
Abstract
LMNA-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 toward 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 Lmna R249W 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.
PMID:
42460417
Bibliographic data and abstract were imported from PubMed on 16 Jul 2026.
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