Targeting nuclear RNA for in vivo correction of myotonic dystrophy

Nuclear-retained transcripts containing expanded repeats are shown to be sensitive to antisense silencing, and in a transgenic mouse model of myotonic dystrophy type 1, systemic administration of ASOs causes a rapid knockdown of the toxic RNA in skeletal muscle, correcting some hallmark features of the disease. A muscular dystrophy rescued by antisense therapy In myotonic dystrophy type I, a common hereditary neuromuscular disorder, the DMPK gene, which normally codes for a protein kinase that is expressed predominantly in skeletal muscle, is mutated in such a way that its transcription results in a toxic RNA molecule that is retained in the nucleus. Charles Thornton and colleagues report the reversal of physical and histological signs of the disease in a mouse model treated with antisense oligonucleotides that caused a rapid knockdown the toxic RNA in skeletal muscle. The effect persisted for up to a year after treatment. Other nuclear-resident RNAs were also sensitive to antisense oligonucleotides, suggesting that this strategy could be used to correct other RNA gain-of-function disorders. Antisense oligonucleotides (ASOs) hold promise for gene-specific knockdown in diseases that involve RNA or protein gain-of-function effects. In the hereditary degenerative disease myotonic dystrophy type 1 (DM1), transcripts from the mutant allele contain an expanded CUG repeat 1 , 2 , 3 and are retained in the nucleus 4 , 5 . The mutant RNA exerts a toxic gain-of-function effect 6 , making it an appropriate target for therapeutic ASOs. However, despite improvements in ASO chemistry and design, systemic use of ASOs is limited because uptake in many tissues, including skeletal and cardiac muscle, is not sufficient to silence target messenger RNAs 7 , 8 . Here we show that nuclear-retained transcripts containing expanded CUG (CUG exp ) repeats are unusually sensitive to antisense silencing. In a transgenic mouse model of DM1, systemic administration of ASOs caused a rapid knockdown of CUG exp RNA in skeletal muscle, correcting the physiological, histopathologic and transcriptomic features of the disease. The effect was sustained for up to 1 year after treatment was discontinued. Systemically administered ASOs were also effective for muscle knockdown of Malat1 , a long non-coding RNA (lncRNA) that is retained in the nucleus 9 . These results provide a general strategy to correct RNA gain-of-function effects and to modulate the expression of expanded repeats, lncRNAs and o