Abstract
Myotonic dystrophy type 1 (DM1) is an autosomal dominant multisystemic disorder caused by expansion of CTG triplet repeats in 3′-untranslated region of DMPK gene. The pathomechanism of DM1 is driven by accumulation of toxic transcripts containing expanded CUG repeats (CUGexp) in nuclear foci which sequester several factors regulating RNA metabolism, such as Muscleblind-like proteins (MBNLs). In this work, we utilized very short chemically modified antisense oligonucleotides composed exclusively of locked nucleic acids (all-LNAs) complementary to CUG repeats, as potential therapeutic agents against DM1. Our in vitro data demonstrated that very short, 8- or 10-unit all-LNAs effectively bound the CUG repeat RNA and prevented the formation of CUGexp/MBNL complexes. In proliferating DM1 cells as well as in skeletal muscles of DM1 mouse model the all-LNAs induced the reduction of the number and size of CUGexp foci and corrected MBNL-sensitive alternative splicing defects with high efficacy and specificity. The all-LNAs had low impact on the cellular level of CUGexp-containing transcripts and did not affect the expression of other transcripts with short CUG repeats. Our data strongly indicate that short all-LNAs complementary to CUG repeats are a promising therapeutic tool against DM1.
Highlights
Myotonic dystrophy type 1 (DM1) is the most common muscular dystrophy in adults, affecting 1 in 6–10 000 live birth
We tested whether very short antisense oligomers composed exclusively of locked nucleic acid (LNA) subunits can efficiently bind to long CUGexp hairpin structure in vitro and in vivo, in order to inhibit pathogenic RNA/protein interaction without causing activation of degradation pathways for long or short carried out by incubating radiolabeled (CUG) repeats-containing transcripts
The stable occupation of CUGexp by LNA is meant to block the excessive binding of proteins such as Muscleblind-like proteins (MBNLs), restoring their normal availability in cellular environment and rescuing cellular processes in which they are involved, such as the alternative splicing regulation
Summary
Myotonic dystrophy type 1 (DM1) is the most common muscular dystrophy in adults, affecting 1 in 6–10 000 live birth. Expanded CUG repeats (CUGexp) interact with RNA-binding proteins such as Muscleblind-like (MBNL) protein family, causing their nuclear sequestration and subsequently resulting in reduced protein activity in several cellular processes [4,5]. Another pathogenic effect of DMPK mutation in DM1 is the induction of post-transcriptional upregulation of another RNA binding protein, CUGBP1 (CELF1). MBNLs and CUGBP1 are antagonistic regulators of alternative splicing, and both control developmentally regulated pre-mRNA maturation of many genes Their functional imbalance leads to embryonic patterns of alternative splicing in adult DM1 tissues [7]
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