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Reversal of RNA toxicity in myotonic dystrophy via a decoy RNA-binding protein with high affinity for expanded CUG repeats

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE189516 | GEO | 2022/01/03

REPOSITORIES: GEO

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Reversal of RNA toxicity in myotonic dystrophy via a decoy RNA-binding protein with high affinity for expanded CUG repeats [mouse]

Project description:Myotonic dystrophy type 1 (DM1) is an RNA-dominant disease whose pathogenesis stems from the functional loss of muscleblind-like RNA-binding proteins (RBPs), which causes the formation of alternative-splicing defects. The loss of functional muscleblind-like protein 1 (MBNL1) results from its nuclear sequestration by mutant transcripts containing pathogenic expanded CUG repeats (CUGexp). Here we show that an MBNL1∆ RBP engineered to act as a decoy for CUGexp reverses the toxicity of the mutant transcripts.

2022-01-03 | GSE189515 | GEO

Reversal of RNA toxicity in myotonic dystrophy via a decoy RNA-binding protein with high affinity for expanded CUG repeats [human]

2022-01-03 | GSE189503 | GEO

Reversal of RNA toxicity in myotonic dystrophy via a decoy RNA-binding protein with high affinity for expanded CUG repeats

Project description:Reversal of RNA toxicity in myotonic dystrophy via a decoy RNA-binding protein with high affinity for expanded CUG repeats

| PRJNA783310 | ENA

Computational investigation of RNA CUG repeats responsible for myotonic dystrophy 1.

Project description:Despite the importance of the knowledge of molecular hydration entropy (ΔShyd) in chemical and biological processes, the exact calculation of ΔShyd is very difficult, because of the complexity in solute–water interactions. Although free-energy perturbation (FEP) methods have been employed quite widely in the literature, the poor convergent behavior of the van der Waals interaction term in the potential function limited the accuracy and robustness. In this study, we propose a new method for estimating ΔShyd by means of combining the FEP approach and the scaled particle theory (or information theory) to separately calculate the electrostatic solute–water interaction term (ΔSelec) and the hydrophobic contribution approximated by the cavity formation entropy (ΔScav), respectively. Decomposition of ΔShyd into ΔScav and ΔSelec terms is found to be very effective with a substantial accuracy enhancement in ΔShyd estimation, when compared to the conventional full FEP calculations. ΔScav appears to dominate over ΔSelec in magnitude, even in the case of polar solutes, implying that the major contribution to the entropic cost for hydration comes from the formation of a solvent-excluded volume. Our hybrid scaled particle theory and FEP method is thus found to enhance the accuracy of ΔShyd prediction by effectively complementing the conventional full FEP method.

| S-EPMC4606397 | biostudies-literature

Reversal of RNA toxicity in myotonic dystrophy via a decoy RNA-binding protein with high affinity for expanded CUG repeats [mouse]

Project description:Reversal of RNA toxicity in myotonic dystrophy via a decoy RNA-binding protein with high affinity for expanded CUG repeats [mouse]

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Reversal of RNA toxicity in myotonic dystrophy via a decoy RNA-binding protein with high affinity for expanded CUG repeats [human]

Project description:Reversal of RNA toxicity in myotonic dystrophy via a decoy RNA-binding protein with high affinity for expanded CUG repeats [human]

| PRJNA783289 | ENA

RNA interference targeting CUG repeats in a mouse model of myotonic dystrophy.

Project description:Myotonic dystrophy type 1 (DM1) is an RNA dominant disease caused by expression of DM protein kinase (DMPK) transcripts that contain an expanded CUG repeat (CUG(exp)). The toxic mRNA localizes to nuclear foci and sequesters proteins involved in the regulation of alternative splicing, such as, muscleblind-like 1 (MBNL1). Here, we used synthetic short interfering RNAs (siRNAs) to target CUG repeats and test the concept that inhibiting the expression of CUG(exp) RNA can mitigate features of DM1 in transgenic mice. Intramuscular injection and electroporation of siRNA resulted in ~70-80% downregulation of CUG(exp) transcripts. A limited survey of endogenous mouse transcripts that contain nonexpanded CUG or CAG repeats showed that most were not affected, though Txlnb containing (CUG)(9) was significantly reduced. By this strategy, the number and intensity of CUG(exp) nuclear foci were reduced and splicing of MBNL1-dependent exons was improved. These data suggest that the expanded CUG repeats are a potential target for allele-selective RNA interference.

| S-EPMC3594017 | biostudies-literature

Actinomycin D Specifically Reduces Expanded CUG Repeat RNA in Myotonic Dystrophy Models.

Project description:Myotonic dystrophy type 1 (DM1) is an inherited disease characterized by the inability to relax contracted muscles. Affected individuals carry large CTG expansions that are toxic when transcribed. One possible treatment approach is to reduce or eliminate transcription of CTG repeats. Actinomycin D (ActD) is a potent transcription inhibitor and FDA-approved chemotherapeutic that binds GC-rich DNA with high affinity. Here, we report that ActD decreased CUG transcript levels in a dose-dependent manner in DM1 cell and mouse models at significantly lower concentrations (nanomolar) compared to its use as a general transcription inhibitor or chemotherapeutic. ActD also significantly reversed DM1-associated splicing defects in a DM1 mouse model, and did so within the currently approved human treatment range. RNA-seq analyses showed that low concentrations of ActD did not globally inhibit transcription in a DM1 mouse model. These results indicate that transcription inhibition of CTG expansions is a promising treatment approach for DM1.

| S-EPMC4691565 | biostudies-literature

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

Project description:Myotonic dystrophy type 1 (DM1) is caused by toxicity of an expanded, noncoding (CUG)n tract in DM protein kinase (DMPK) transcripts. According to current evidence the long (CUG)n segment is involved in entrapment of muscleblind (Mbnl) proteins in ribonuclear aggregates and stabilized expression of CUG binding protein 1 (CUGBP1), causing aberrant premRNA splicing and associated pathogenesis in DM1 patients. Here, we report on the use of antisense oligonucleotides (AONs) in a therapeutic strategy for reversal of RNA-gain-of-function toxicity. Using a previously undescribed mouse DM1 myoblast-myotube cell model and DM1 patient cells as screening tools, we have identified a fully 2'-O-methyl-phosphorothioate-modified (CAG)7 AON that silences mutant DMPK RNA expression and reduces the number of ribonuclear aggregates in a selective and (CUG)n-length-dependent manner. Direct administration of this AON in muscle of DM1 mouse models in vivo caused a significant reduction in the level of toxic (CUG)n RNA and a normalizing effect on aberrant premRNA splicing. Our data demonstrate proof of principle for therapeutic use of simple sequence AONs in DM1 and potentially other unstable microsatellite diseases.

| S-EPMC2728995 | biostudies-literature

Treatment of type 1 myotonic dystrophy by engineering site-specific RNA endonucleases that target (CUG)(n) repeats.

Project description:Myotonic dystrophy type 1 (DM1) is caused by the expansion of (CTG)n in the 3' untranslated region of the dystrophia myotonica-protein kinase (DMPK) gene, which is transcribed as (CUG)n repeats that accumulate in the nucleus. The RNA repeats specifically sequester or change the expression levels of several RNA-binding proteins, leading to aberrant splicing of many target genes. In this study, we developed artificial site-specific RNA endonucleases (ASREs) that specifically bind and cleave (CUG)n repeats RNA. We have generated one ASRE that can target the expanded RNA repeats in DM1 patient cells and specifically degrade the pathogenic DMPK messenger RNAs with minimal effect on wild-type alleles. Such ASRE treatment significantly decreased the number of nuclear foci in DM1 patient cells and can reverse the missplicing of many genes affected in DM1 patients. Taken together, the application of ASRE provides a new route of gene therapy for DM1 treatment.

| S-EPMC3916045 | biostudies-literature

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