Gene-editing in patient and humanized-mice primary muscle stem cells rescues dysferlin expression in dysferlin-deficient muscular dystrophy

Helena Escobar (), Silvia Di Francescantonio, Julia Smirnova, Robin Graf, Stefanie Müthel, Andreas Marg, Alexej Zhogov, Supriya Krishna, Eric Metzler, Mina Petkova, Oliver Daumke, Ralf Kühn and Simone Spuler ()
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Helena Escobar: Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC)
Silvia Di Francescantonio: Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC)
Julia Smirnova: Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC)
Robin Graf: Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC)
Stefanie Müthel: Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC)
Andreas Marg: Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC)
Alexej Zhogov: Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC)
Supriya Krishna: Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC)
Eric Metzler: Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC)
Mina Petkova: MyoPax GmbH
Oliver Daumke: Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC)
Ralf Kühn: Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC)
Simone Spuler: Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC)

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: Abstract Dystrophy-associated fer-1-like protein (dysferlin) conducts plasma membrane repair. Mutations in the DYSF gene cause a panoply of genetic muscular dystrophies. We targeted a frequent loss-of-function, DYSF exon 44, founder frameshift mutation with mRNA-mediated delivery of SpCas9 in combination with a mutation-specific sgRNA to primary muscle stem cells from two homozygous patients. We observed a consistent >60% exon 44 re-framing, rescuing a full-length and functional dysferlin protein. A new mouse model harboring a humanized Dysf exon 44 with the founder mutation, hEx44mut, recapitulates the patients’ phenotype and an identical re-framing outcome in primary muscle stem cells. Finally, gene-edited murine primary muscle stem-cells are able to regenerate muscle and rescue dysferlin when transplanted back into hEx44mut hosts. These findings are the first to show that a CRISPR-mediated therapy can ameliorate dysferlin deficiency. We suggest that gene-edited primary muscle stem cells could exhibit utility, not only in treating dysferlin deficiency syndromes, but also perhaps other forms of muscular dystrophy.

Date: 2025
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DOI: 10.1038/s41467-024-55086-0

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