Targeting nuclear RNA for in vivo correction of myotonic dystrophy


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 repeat1,2,3 and are retained in the nucleus4,5. The mutant RNA exerts a toxic gain-of-function effect6, 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 RNAs7,8. Here we show that nuclear-retained transcripts containing expanded CUG (CUGexp) repeats are unusually sensitive to antisense silencing. In a transgenic mouse model of DM1, systemic administration of ASOs caused a rapid knockdown of CUGexp 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 nucleus9. These results provide a general strategy to correct RNA gain-of-function effects and to modulate the expression of expanded repeats, lncRNAs and other transcripts with prolonged nuclear residence.

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Figure 1: Systemic administration of 2′- O -(2-methoxyethyl) ASOs in the HSA LR transgenic mouse model of DM1.
Figure 2: Effects of ASOs on the transcriptome in quadriceps muscle.
Figure 3: Differential sensitivity of transcripts to ASO knockdown in skeletal muscle.
Figure 4: Duration of ASO activity and in vivo targeting of human DMPK.


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The work was carried out at the Wellstone Muscular Dystrophy Cooperative Research Center and Center for RNA Biology at the University of Rochester, with support from the US National Institutes of Health (NIH) (grants AR049077, U54NS48843, AR/NS48143, K08NS064293 and U01NS072323), the Saunders Family Neuromuscular Research Fund, Run America and a fellowship (to M.N.) from the Muscular Dystrophy Association and Uehara Memorial Foundation. The authors thank G. Gourdon for providing DM328XL mice, M. Sabripour for assistance with principal components analysis and L. Richardson and S. Leistman for technical assistance.

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Author Contributions T.M.W., A.J.L, S.K.P., A.R.M., M.N., S.H.C., B.M.W., C.F.B. and C.A.T. participated in the planning, design and interpretation of experiments. T.M.W., A.J.L., S.K.P., A.R.M and M.N. carried out experiments. T.M.W. and C.A.T. wrote the manuscript.

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Correspondence to Charles A. Thornton.

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Competing interests

S.K.P., A.R.M. and C.F.B. are employees of Isis Pharmaceuticals, which develops antisense drugs. A.J.L., S.H.C. and B.M.W. are employees of Genzyme Corporation, which develops biological therapeutics. C.A.T. and T.M.W. received research support from Isis Pharmaceuticals. Isis Pharmaceuticals has applied for patents related to this work.

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Wheeler, T., Leger, A., Pandey, S. et al. Targeting nuclear RNA for in vivo correction of myotonic dystrophy. Nature 488, 111–115 (2012).

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