The sustained expression of Cas9 targeting toxic RNAs reverses disease phenotypes in mouse models of myotonic dystrophy type 1
- 14 September 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Biomedical Engineering
- Vol. 5 (2), 157-168
- https://doi.org/10.1038/s41551-020-00607-7
Abstract
Myotonic dystrophy type I (DM1) is a multisystemic autosomal-dominant inherited human disorder that is caused by CTG microsatellite repeat expansions (MREs) in the 3′ untranslated region of DMPK. Toxic RNAs expressed from such repetitive sequences can be eliminated using CRISPR-mediated RNA targeting, yet evidence of its in vivo efficacy and durability is lacking. Here, using adult and neonatal mouse models of DM1, we show that intramuscular or systemic injections of adeno-associated virus (AAV) vectors encoding nuclease-dead Cas9 and a single-guide RNA targeting CUG repeats results in the expression of the RNA-targeting Cas9 for up to three months, redistribution of the RNA-splicing protein muscleblind-like splicing regulator 1, elimination of foci of toxic RNA, reversal of splicing biomarkers and amelioration of myotonia. The sustained reversal of DM1 phenotypes provides further support that RNA-targeting Cas9 is a viable strategy for treating DM1 and other MRE-associated diseases.Keywords
Funding Information
- U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NS103172, NS103172, NS103172, NS103172, NS103172, NS103172, NS103172, NS103172, NS103172, NS103172)
- Muscular Dystrophy Association (MVP575855, MVP575855, MVP575855)
- Locana, Inc. is a privately funded biotechnology start up in San Digeo.
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