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

Molecular Therapy: Nucleic Acids

Aline Lachon¹  Geneviève Gourdon¹  Lucille Revillod²  Guillaume Bassez²  Sanjay K. Pandey³  C. Frank Bennett³  A. Robert McLeod³  Dominic Jauvin⁴  Laurie Martineau⁴  Jack Puymirat⁴  Jessina Chrétien⁴  Thurman M. Wheeler⁵  Charles A. Thornton⁶ 

[1] INSERM U781, Imagine Institute, Paris 75015, France;INSERM U955, Neuromuscular Reference Center, Henri-Mondor Hospital, Créteil 94000, France;Ionis Pharmaceuticals, Inc., Carlsbad, CA 92010, USA;Laval University Experimental Organogenesis Center/LOEX, Enfant-Jésus Hospital, Québec, QC G1J 1Z4, Canada;Massachusetts General Hospital, Boston, MA 02114-3117, USA;University of Rochester Medical Center, Rochester, NY 14642, USA;

关键词: myotonic dystrophy;    gene therapy;    oligonucleotide;    muscle;    muscular dystrophy;   

DOI  :  10.1016/j.omtn.2017.05.007

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown