Key result
CRISPR-Cas9 gene editing extends median survival ~24% and improves cardiac pathology in Lmna-mutant mice.
Why the study?
LMNA-associated congenital muscular dystrophy is an incurable rare genetic disorder resulting from LMNA mutations and characterized by early-onset muscle weakness, dilated cardiomyopathy, and respiratory failure.
Does CRISPR-Cas9-mediated gene editing targeting the Lmna c.745C>T mutation improve survival and cardiac function in Lmna R249W mice?
Does CRISPR-Cas9-mediated gene editing targeting the Lmna c.745C>T mutation improve survival and cardiac function in Lmna R249W mice?
CRISPR-Cas9-mediated gene editing targeting the Lmna c.745C>T mutant allele improves survival and cardiac pathology in a mouse model of LMNA-associated congenital muscular dystrophy.
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. Pérez de Castro and colleagues validate a CRISPR-Cas9-based therapeutic strategy to target the Lmna c.745C>T mutant allele in cellular models and mice, improving survival and cardiac pathology in LMNA -associated congenital muscular dystrophy.
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Gómez-Domínguez et al. (2025) studied LMNA-associated congenital muscular dystrophy. CRISPR-Cas9-mediated gene editing (sg745T) was evaluated on Survival and cardiac pathology (24.3% extension of median survival). A CRISPR-Cas9-mediated gene editing strategy targeting the Lmna c.745C>T mutant allele significantly ameliorated cardiac pathology and extended median survival by 24.3% in Lmna +/R249W mice.
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