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CRISPR/Cas Applications in Myotonic Dystrophy: Expanding Opportunities

1
Department of Cell Biology, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, 6525 GA Nijmegen, The Netherlands
2
Department of Human Genetics, Radboud University Medical Center, Donders Institute for Brain Cognition and Behavior, 6525 GA Nijmegen, The Netherlands
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Int. J. Mol. Sci. 2019, 20(15), 3689; https://doi.org/10.3390/ijms20153689
Received: 4 June 2019 / Revised: 24 July 2019 / Accepted: 25 July 2019 / Published: 27 July 2019
(This article belongs to the Special Issue Myotonic Dystrophy: From Molecular Pathogenesis to Therapeutics)
CRISPR/Cas technology holds promise for the development of therapies to treat inherited diseases. Myotonic dystrophy type 1 (DM1) is a severe neuromuscular disorder with a variable multisystemic character for which no cure is yet available. Here, we review CRISPR/Cas-mediated approaches that target the unstable (CTG•CAG)n repeat in the DMPK/DM1-AS gene pair, the autosomal dominant mutation that causes DM1. Expansion of the repeat results in a complex constellation of toxicity at the DNA level, an altered transcriptome and a disturbed proteome. To restore cellular homeostasis and ameliorate DM1 disease symptoms, CRISPR/Cas approaches were directed at the causative mutation in the DNA and the RNA. Specifically, the triplet repeat has been excised from the genome by several laboratories via dual CRISPR/Cas9 cleavage, while one group prevented transcription of the (CTG)n repeat through homology-directed insertion of a polyadenylation signal in DMPK. Independently, catalytically deficient Cas9 (dCas9) was recruited to the (CTG)n repeat to block progression of RNA polymerase II and a dCas9-RNase fusion was shown to degrade expanded (CUG)n RNA. We compare these promising developments in DM1 with those in other microsatellite instability diseases. Finally, we look at hurdles that must be taken to make CRISPR/Cas-mediated editing a therapeutic reality in patients. View Full-Text
Keywords: cell therapy; gene editing; gene therapy; muscular dystrophy; myotonic dystrophy; neuromuscular disease; repeat expansion; trinucleotide repeat cell therapy; gene editing; gene therapy; muscular dystrophy; myotonic dystrophy; neuromuscular disease; repeat expansion; trinucleotide repeat
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MDPI and ACS Style

Raaijmakers, R.H.; Ripken, L.; Ausems, C.R.M.; Wansink, D.G. CRISPR/Cas Applications in Myotonic Dystrophy: Expanding Opportunities. Int. J. Mol. Sci. 2019, 20, 3689.

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