Targeting CAG repeat RNAs reduces Huntington’s disease phenotype independently of huntingtin levels

Rué, Laura; Báñez-Coronel, Mónica; Creus-Muncunill, Jordi; Giralt, Albert; Alcalà-Vida, Rafael; Mentxaka, Gartze; Kagerbauer, Birgit; Zomeño-Abellán, M. Teresa; Aranda, Zeus; Venturi, Veronica; Pérez‐Navarro, Esther; Estivill, Xavier; Martı́, Eulàlia

doi:10.1172/jci83185

Cited by 63 publications

(51 citation statements)

References 57 publications

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“…RNA foci were not detected after RNase treatment (Supplementary Figure S2). As shown for LNA reagents, for which their binding to repeat sequences may block subsequent RT-PCR (Rué et al, 2016), we demonstrated that the reagents did not interfere with the RNA FISH procedure by visualizing HTT mRNA with HTT sequence-specific probes. Probes targeting the first exon of HTT mRNA were used to successfully visualize RNA foci in HD fibroblasts.…”

Section: Resultssupporting

confidence: 66%

“…LNA CTG treatment led to rescue of lowered levels of striatal markers and improved motor functions in HD mouse model. It was also shown that used ON was able to decrease number of foci-positive cells (Rué et al, 2016). LNA CTG may prevent mRNAs from RNA foci formation or release transcripts from foci by interfering with interactions between CAG tracts and proteins.…”

Section: Discussionmentioning

confidence: 98%

“…Multiple therapeutic approaches have been proposed for polyQ diseases (reviewed in Fiszer and Krzyzosiak, 2014; Keiser et al, 2016), but their effects on nuclear RNA foci have been barely analyzed. To date, only a single recent report refers to foci reduction, showing that 20-nt-long LNA-modified ON composed of CTG units disrupts CAG RNA foci in an HD model (Rué et al, 2016). …”

Section: Introductionmentioning

confidence: 99%

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Reduction of Huntington’s Disease RNA Foci by CAG Repeat-Targeting Reagents

Urbanek

Fiszer

Krzyżosiak

2017

Front. Cell. Neurosci.

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In several human polyglutamine diseases caused by expansions of CAG repeats in the coding sequence of single genes, mutant transcripts are detained in nuclear RNA foci. In polyglutamine disorders, unlike other repeat-associated diseases, both RNA and proteins exert pathogenic effects; therefore, decreases of both RNA and protein toxicity need to be addressed in proposed treatments. A variety of oligonucleotide-based therapeutic approaches have been developed for polyglutamine diseases, but concomitant assays for RNA foci reduction are lacking. Here, we show that various types of oligonucleotide-based reagents affect RNA foci number in Huntington’s disease cells. We analyzed the effects of reagents targeting either CAG repeat tracts or specific HTT sequences in fibroblasts derived from patients. We tested reagents that either acted as translation blockers or triggered mRNA degradation via the RNA interference pathway or RNase H activation. We also analyzed the effect of chemical modifications of CAG repeat-targeting siRNAs on their efficiency in the foci decline. Our results suggest that the decrease of RNA foci number may be considered as a readout of treatment outcomes for oligonucleotide reagents.

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Section: Resultssupporting

confidence: 66%

Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

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Reduction of Huntington’s Disease RNA Foci by CAG Repeat-Targeting Reagents

Urbanek

Fiszer

Krzyżosiak

2017

Front. Cell. Neurosci.

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“…to neural cells (Bañ ez-Coronel et al, 2015). Finally, the CAGexpanded HTT mRNA may itself contribute to HD toxicity (Rué et al, 2016). The relative contribution of these alternate mechanisms to overall HD pathogenesis is not yet clear but should be borne in mind because they might evade some of the current approaches used for HTT lowering (Figure 1).…”

Section: Reviewmentioning

confidence: 99%

Huntingtin Lowering Strategies for Disease Modification in Huntington’s Disease

Tabrizi

Ghosh

Leavitt

2019

Neuron

261

190

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“…Hu et al [50] observed that LNAs, as well as previously described PNAs, can confer potent allele-selective inhibition of mutant huntingtin gene expression [50]. In the same way, Rué et al [52] observed that a LNA-modified antisense oligonucleotide complementary to the CAG-repeat (LNA-CTG) preferentially bound to mutant htt gene without affecting wild-type HTT mRNA or protein levels. Furthermore, these researchers observed that this strategy promotes neuroprotection in a mouse model of HD by blocking the detrimental activity of CAG-repeats in the htt gene [52].…”

Section: Dna Targeting Strategiesmentioning

confidence: 88%

Experimental DNA- or RNA-Directed Therapies for Trinucleotide Repeat Disease

Cardoso¹

2018

obm genet

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Some repeats of three or more nucleotides in tandem, which are present in a gene or in its vicinity, tend to increase in number and for this reason are called dynamic mutations. These triplet repeats are unstable and can expand from one generation to the next. According to the expansion size, an unaffected individual can carry a pre-mutation that will expand through generations leading to the development of triplet repeat expansion diseases. The increase in the number of repeats over time leads to earlier development and increased severity of symptoms in affected individuals in successive generations. Although there is still no treatment for this type of disease, several strategies are under investigation. Here, we describe treatment approaches for triplet repeat expansion diseases that have been developed over recent years, using DNA or RNA molecules as targets. Some of these strategies have the potential for future use in gene therapy for trinucleotide repeat disorders.

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Targeting CAG repeat RNAs reduces Huntington’s disease phenotype independently of huntingtin levels

Cited by 63 publications

References 57 publications

Reduction of Huntington’s Disease RNA Foci by CAG Repeat-Targeting Reagents

Reduction of Huntington’s Disease RNA Foci by CAG Repeat-Targeting Reagents

Huntingtin Lowering Strategies for Disease Modification in Huntington’s Disease

Experimental DNA- or RNA-Directed Therapies for Trinucleotide Repeat Disease

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