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Mol Ther Nucleic Acids. 2017 Jun 16;7:465-474. doi: 10.1016/j.omtn.2017.05.007. Epub 2017 May 17.

Targeting DMPK with Antisense Oligonucleotide Improves Muscle Strength in Myotonic Dystrophy Type 1 Mice.

Author information

1
Laval University Experimental Organogenesis Center/LOEX, Enfant-Jésus Hospital, Québec, QC G1J 1Z4, Canada.
2
Ionis Pharmaceuticals, Inc., Carlsbad, CA 92010, USA; Triangulum Biopharma, San Diego, CA 92121, USA.
3
INSERM U955, Neuromuscular Reference Center, Henri-Mondor Hospital, Créteil 94000, France.
4
INSERM U781, Imagine Institute, Paris 75015, France.
5
Ionis Pharmaceuticals, Inc., Carlsbad, CA 92010, USA.
6
Massachusetts General Hospital, Boston, MA 02114-3117, USA.
7
University of Rochester Medical Center, Rochester, NY 14642, USA.
8
Laval University Experimental Organogenesis Center/LOEX, Enfant-Jésus Hospital, Québec, QC G1J 1Z4, Canada; Department of Neurological Sciences CHU de Québec-Laval University, Enfant-Jésus Hospital, Québec, QC G1J 1Z4, Canada. Electronic address: jack.puymirat@crchudequebec.ulaval.ca.

Abstract

Myotonic dystrophy type 1 (DM1), a dominant hereditary muscular dystrophy, is caused by an abnormal expansion of a (CTG)n trinucleotide repeat in the 3' UTR of the human dystrophia myotonica protein kinase (DMPK) gene. As a consequence, mutant transcripts containing expanded CUG repeats are retained in nuclear foci and alter the function of splicing regulatory factors members of the MBNL and CELF families, resulting in alternative splicing misregulation of specific transcripts in affected DM1 tissues. In the present study, we treated DMSXL mice systemically with a 2'-4'-constrained, ethyl-modified (ISIS 486178) antisense oligonucleotide (ASO) targeted to the 3' UTR of the DMPK gene, which led to a 70% reduction in CUGexp RNA abundance and foci in different skeletal muscles and a 30% reduction in the heart. Furthermore, treatment with ISIS 486178 ASO improved body weight, muscle strength, and muscle histology, whereas no overt toxicity was detected. This is evidence that the reduction of CUGexp RNA improves muscle strength in DM1, suggesting that muscle weakness in DM1 patients may be improved following elimination of toxic RNAs.

KEYWORDS:

gene therapy; muscle; muscular dystrophy; myotonic dystrophy; oligonucleotide

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