Allele-Specific RNA Silencing of Mutant Ataxin-3 Mediates Neuroprotection in a Rat Model of Machado-Joseph Disease

Alves, Sandro; Nascimento-Ferreira, Isabel; Aurégan, Gwenaëlle; Hässig, Raymonde; Dufour, Noëlle; Brouillet, Emmanuel; Lima, Maria C. Pedroso de; Hantraye, Philippe; Almeida, Luís Pereira de; Déglon, Nicole

doi:10.1371/journal.pone.0003341

Cited by 147 publications

(132 citation statements)

References 37 publications

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“…More recently, our group showed both in vitro and in a rat model of MJD that lentiviral-mediated silencing of the mutant human ataxin-3 was efficient and selective, allowing preservation of wild-type ataxin-3 (Alves et al, 2008a). Specific silencing has also been later reported to SNPs targeting ataxin-7 in SCA7 (Scholefield et al, 2009) and huntingtin in Huntington's disease (Zhang et al, 2009;Hu et al, 2009).…”

Section: Rna Interference-based Therapeuticsmentioning

confidence: 96%

“…RNA interference (RNAi) is a powerful tool for selective knockdown of gene expression. Gene silencing by RNAi has been successfully used to downregulate the expression of mutant genes and rescue phenotype in various neurodegenerative diseases, including Huntington's disease Rodriguez-Lebron et al, 2005;DiFiglia et al, 2007, van Bilsen et al, 2008Lombardi et al, 2009;Pfister et al, 2009), familial forms of amyotrophic lateral sclerosis (ALS) (Raoul et al, 2005;Ralph et al, 2005;Azzouz, 2006), SCA1 (Xia et al, 2004), and MJD (Miller et al, 2003;Alves et al, 2008aAlves et al, , 2010Hu et al, 2009). …”

Section: Rna Interference-based Therapeuticsmentioning

confidence: 99%

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Machado-Joseph Disease / Spinocerebellar Ataxia Type 3

Nóbrega¹,

Almeida²

2012

Spinocerebellar Ataxia

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Section: Rna Interference-based Therapeuticsmentioning

confidence: 96%

Section: Rna Interference-based Therapeuticsmentioning

confidence: 99%

Machado-Joseph Disease / Spinocerebellar Ataxia Type 3

Nóbrega¹,

Almeida²

2012

Spinocerebellar Ataxia

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“…The therapeutic utility of RNAi for SCA3 was first tested in the rat by targeting a SNP in the mutant allele. Reducing levels of the mutant allele rescued diseased phenotypes [104]. Later, work from the same group showed that shRNAs designed to be nonallele-specific, silenced both wild type and mutant ataxin-3, and rescued SCA3 phenotypes.…”

Section: Spinocerebellar Ataxia Typementioning

confidence: 99%

Recent Advances in RNA Interference Therapeutics for CNS Diseases

2013

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Over the last decade, RNA interference technology has shown therapeutic promise in rodent models of dominantly inherited brain diseases, including those caused by polyglutamine repeat expansions in the coding region of the affected gene. For some of these diseases, proof-of concept studies in model organisms have transitioned to safety testing in larger animal models, such as the nonhuman primate. Here, we review recent progress on RNA interference-based therapies in various model systems. We also highlight outstanding questions or concerns that have emerged as a result of an improved (and ever advancing) understanding of the technologies employed.

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“…This specificity was achieved through lentiviral vectors encoding siRNAs that selectively target a SNP that occurs in over 70% of SCA3 patients. This allele specific mechanism decreased the severity of neurological pathogenesis associated with SCA3 [215]. Furthermore, independent studies used a similar mechanism, adeno-associated viral (AAV) vector based delivery of shRNA and small interfering RNA (siRNA) to rescue phenotypes in SCA1 [216] and SCA7 in affected mouse models, respectively.…”

Section: Suppression/modification Of Mutant Gene Expression and Protementioning

confidence: 99%

Polyglutamine ataxias: From Clinical and Molecular Features to Current Therapeutic Strategies

McIntosh¹,

Htut²,

Fletcher³

et al. 2017

J Genet Syndr Gene Ther

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Spinocerebellar ataxias are a large group of heterogeneous diseases that all involve selective neuronal degeneration and accompanied cerebellar ataxia. These diseases can be further broken down into discrete groups according to their underlying molecular genetic cause. The most common are the polyglutamine ataxias, of which there are six; Spinocerebellar ataxia type 1, 2, 3, 6, 7 and 17. These diseases are characterised by a pathological expanded cytosine-adenine-guanine (CAG) repeat sequence, in the protein coding region of a given gene. Common clinical features include lack of coordination and gait ataxia, speech and swallowing difficulties, as well as impaired hand and motor functions. The polyglutamine spinocerebellar ataxias are typically late onset diseases that are progressive in nature and often lead to premature death, for which there is currently no known cure or effective treatment strategy. Although caused by the same molecular mechanism, the causative gene and associated protein differ for each disease. The exact mechanism by which disease pathogenesis is caused remains elusive. However, the variable (CAG) n repeats are codons that may be translated to an expanded glutamine tract, leading to conformational changes in the protein, giving it a toxic gain of function. Several pathogenic pathways have been implicated in polyglutamine spinocerebellar ataxia diseases, such as the hallmark feature of neuronal nuclear inclusions, protein misfolding and aggregation, as well as transcriptional dysregulation. These pathways are attractive avenues for potential therapeutic interventions, as the potential to treat more than one disease exists. Research is ongoing, and several promising therapies are currently underway in an attempt to provide relief for this devastating class of diseases.. However, mutations can arise de novo, through errors in DNA replication such that two genetically healthy parents can give rise to an affected child.There are currently six characterised polyQ SCAs (1, 2, 3, 6, 7 and 17) (Table 1), and together with three other diseases, namely Huntington's disease, spinal and bulbar muscular atrophy and dentatorubropallidoluysian atrophy (DRPLA), form a larger category of polyQ diseases [7][8][9][10]. Th ere is little relief for individuals suffering from polyQ SCA disorders, with symptomatic treatments the only available option. Long term pharmacological treatment, although admirable, tends to fall short in an effective management strategy, as unwanted complications and low drug efficacy still exist. In addition, none of these diseases have any treatments that slow the progression of the disease; leaving affected individuals with the daunting reality that time may be a severe limiting factor. Several experimental approaches are currently being assessed to overcome these difficulties. This review will focus on the clinical and molecular features of polyQ SCA diseases (which will be referred to as SCA diseases), as well as highlight several promising and emerging therapeutic strategies...

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Allele-Specific RNA Silencing of Mutant Ataxin-3 Mediates Neuroprotection in a Rat Model of Machado-Joseph Disease

Cited by 147 publications

References 37 publications

Machado-Joseph Disease / Spinocerebellar Ataxia Type 3

Machado-Joseph Disease / Spinocerebellar Ataxia Type 3

Recent Advances in RNA Interference Therapeutics for CNS Diseases

Polyglutamine ataxias: From Clinical and Molecular Features to Current Therapeutic Strategies

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