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bioRxiv · 10.1101/184408

Reversal of molecular pathology by RNA-targeting Cas9 in a myotonic dystrophy mouse model

Batra, R.·Nelles, D. A.·Krach, F.·Thomas, J. D.·Snjader, L.·Blue, S. M.·Aigner, S.·Swanson, M. S.·Yeo, G. W.
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Abstract

The dominantly inherited, multi-systemic disease myotonic dystrophy type I (DM1) is caused by triplet repeat CTG expansions in the DMPK gene and is the most common form of adult-onset muscular dystrophy. Elimination of the toxic, repetitive CUG RNA constitutes a therapeutic for this disease. We report an RNA-targeting Cas9 (RCas9) system that supports efficient reversal of DM1 phenotypes via delivery to adult poly(CUG) DM1 mouse muscle using adeno-associated virus (AAV). We observe elimination of CUG RNA, restoration of CUG foci-associated Mbnl1 protein to wild-type subcellular localization, correction of DM1-type alternative splicing patterns in candidate genes including the voltage-gated chloride channel 1 (Clcn1) responsible for characteristic myotonia, recovery of Clcn1 staining, and reduction in centralized myonuclei. Our results establish RCas9 as a potential long-term in vivo therapeutic for DM1.\n\nOne Sentence SummaryA repurposed CRISPR system termed RNA-targeting Cas9 reverses the molecular pathology associated with the most common type of adult onset muscular dystrophy in adult mouse muscle.

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Batra, R., Nelles, D. A., Krach, F., Thomas, J. D., Snjader, L., Blue, S. M., Aigner, S., Swanson, M. S., Yeo, G. W.. 2017-09-04. Reversal of molecular pathology by RNA-targeting Cas9 in a myotonic dystrophy mouse model. https://doi.org/10.1101/184408

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