Triplet-repeat oligonucleotide-mediated reversal of RNA toxicity in myotonic dystrophy

Mulders, Susan A. M.; Broek, W.J.A.A. van den; Wheeler, Thurman M.; Croes, H.J.E.; Kuik-Romeijn, Petra van; Kimpe, Sjef J. De; Furling, Denis; Platenburg, Gerard; Gourdon, Geneviève; Thornton, Charles A.; Wieringa, Bé; Wansink, Derick G.

doi:10.1073/pnas.0905780106

Cited by 233 publications

(223 citation statements)

References 25 publications

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“…We found that fluorescently tagged ASOs transfected into cultured cells localize predominantly in the nucleus, consistent with previous results (27). Moreover, 2′-OMe ASOs injected in mouse muscle are concentrated in nuclei (13). It seems likely that a large fraction of the gapmers retained in muscle enter the nucleus given the 50% reduction of CUG RNA.…”

Section: Discussionsupporting

confidence: 80%

“…2′-OMe ASOs have also been shown to selectively target expanded CUG repeats in DM1 myoblasts (13). Another study showed that ASOs used to inhibit translation of CAG expansions in Huntington disease only affected the expanded huntingtin allele but not the wild-type allele (26).…”

Section: Discussionmentioning

confidence: 99%

“…We designed the gapmers for RNase H accessibility; however, previous studies have shown that ASOs can also initiate degradation through RNase H-independent pathways (12,13). To determine whether the effect of the CAG gapmers is dependent on accessibility to RNase H, we tested a CAG "mixmer" (CAGmix) containing MOE and PS modifications that do not form a gap of more than 3 nucleotides, preventing binding of RNase H (15).…”

Section: Rnase H-mediated Degradation Of Expanded Cug Repeats In Cellmentioning

confidence: 99%

“…We next tested whether there are off-target effects on endogenous transcripts containing CUG repeats. There are at least eleven genes in mice that express mRNAs containing ≥ 6 CUG repeats (12,13). To determine the nontarget effect of the gapmers, we examined the mRNA levels of three genes: Mapkap1, Mllt3 and Pcolce, which contain 26, 8 and 12 CUG repeats respectively.…”

Section: Cag Gapmers Induce Histological Abnormalities In Mouse Skeletalmentioning

confidence: 99%

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RNase H-mediated degradation of toxic RNA in myotonic dystrophy type 1

Lee

Bennett

Cooper

2012

Proc. Natl. Acad. Sci. U.S.A.

142

133

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Myotonic dystrophy type 1 (DM1) is an RNA-dominant disease caused by abnormal transcripts containing expanded CUG repeats. The CUG transcripts aggregate in the nucleus to form RNA foci and lead to nuclear depletion of Muscleblind-like 1 (MBNL1) and stabilized expression of CUGBP Elav like family 1 (CELF1), both of which are splicing regulatory proteins. The imbalance of these proteins results in misregulation of alternative splicing and neuromuscular abnormalities. Here, we report the use of antisense oligonucleotides (ASOs) as a therapeutic approach to target the pathogenic RNA in DM1. We designed chimeric ASOs, termed gapmers, containing modified nucleic acid residues to induce RNase H-mediated degradation of CUG-repeat transcripts. The gapmers selectively knockdown expanded CUG transcripts and are sufficient to disrupt RNA foci both in cell culture and mouse models for DM1. Furthermore, combination of gapmers with morpholino ASOs that help release binding of MBNL1 to the toxic RNA can potentially enhance the knockdown effect. Additional optimization will be required for systemic delivery; however, our study provides an alternative strategy for the use of ASOs in DM1 therapy.microsatellite expansion | muscular dystrophy | phosphorothioate | gapmer

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Section: Discussionsupporting

confidence: 80%

Section: Discussionmentioning

confidence: 99%

Section: Rnase H-mediated Degradation Of Expanded Cug Repeats In Cellmentioning

confidence: 99%

Section: Cag Gapmers Induce Histological Abnormalities In Mouse Skeletalmentioning

confidence: 99%

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RNase H-mediated degradation of toxic RNA in myotonic dystrophy type 1

Lee

Bennett

Cooper

2012

Proc. Natl. Acad. Sci. U.S.A.

142

133

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“…A recent report showed convincingly the therapeutic effect of 2 -O-methyl phosphorothioatemodified (CAG)7 oligonucleotides in DM1 mouse models and in patient myoblast cultures (Mulders et al, 2009). The addition of 2 -O-methyl groups to a phosphorothioate-modified oligonucleotide confers increased stability of binding and reduced nonspecific effects.…”

Section: Destroying or Blocking The Function Of Mutant Dmpk Transcriptsmentioning

confidence: 99%

Tackling the pathogenesis of RNA nuclear retention in myotonic dystrophy

Mastroyiannopoulos

Shammas

Phylactou

2010

Biology of the Cell

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Cyprus DM1 (myotonic dystrophy type I) is a common form of muscular dystrophy that affects mainly adults. It is a disease that belongs to the group of defective RNA export diseases, since a major part of the pathogenic mechanism of the disease is the retention of the mutant transcripts in the cell nucleus. The presence of an expanded CUG trinucleotide repeat in the 3 -UTR (3 -untranslated region) of the DMPK (myotonic dystrophy protein kinase) gene causes the attraction of RNA-binding proteins by the nuclear-located mutant transcripts. As a result of the occupation of the RNA-binding proteins, there is defective mis-splicing of several cellular transcripts. This is believed to be a major pathogenic mechanism of the disease and any attempt to repair the activities of the RNA-binding proteins or target the mutant transcripts should be beneficial for the patients. Certain approaches have been described in the literature and they demonstrate progress in various directions. The purpose of the present review is to summarize the successful attempts to tackle the pathogenesis caused by nuclear retention of mutant transcripts in myotonic dystrophy and to discuss the possible gains from such approaches.

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