RNAi suppresses polyglutamine-induced neurodegeneration in a model of spinocerebellar ataxia

Xia, Haibin; Mao, Qinwen; Eliason, Steven; Harper, Scott Q.; Martins, Inês; Orr, Harry T.; Paulson, Henry L.; Yang, Linda; Kotin, Robert M.; Davidson, Beverly L.

doi:10.1038/nm1076

Cited by 621 publications

(429 citation statements)

References 24 publications

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“…6,11,21 However, only a few studies have assessed silencing in patient-derived cells, which exhibit physiologically relevant levels of endogenous expression. 3,[22][23][24][25] We sought to address whether polyQ patient-derived fibroblasts might be a useful model for assessing therapeutic strategies, such as comparing allele-specific and non-allele-specific silencing approaches in genetically accurate cells.…”

Section: Discussionmentioning

confidence: 99%

“…Several studies have demonstrated the potential of RNA interference (RNAi) based silencing as a therapeutic approach for HD, SCA1, SCA3, SCA6 and SCA7. [2][3][4][5][6][7][8][9][10][11] However, most of these reports have used overexpression models or transgenic animal models to demonstrate efficacy-models which fail to mimic the precise genomic context of mutation found in patients. These models have also failed to provide answers to important questions regarding the necessity and feasibility of allele-specific silencing of the mutant transcript alone, without concomitant silencing of the wild type.…”

Section: Introductionmentioning

confidence: 99%

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Allele-specific silencing of mutant Ataxin-7 in SCA7 patient-derived fibroblasts

et al. 2014

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Polyglutamine (polyQ) disorders are inherited neurodegenerative conditions defined by a common pathogenic CAG repeat expansion leading to a toxic gain-of-function of the mutant protein. Consequences of this toxicity include activation of heatshock proteins (HSPs), impairment of the ubiquitin-proteasome pathway and transcriptional dysregulation. Several studies in animal models have shown that reducing levels of toxic protein using small RNAs would be an ideal therapeutic approach for such disorders, including spinocerebellar ataxia-7 (SCA7). However, testing such RNA interference (RNAi) effectors in genetically appropriate patient cell lines with a disease-relevant phenotype has yet to be explored. Here, we have used primary adult dermal fibroblasts from SCA7 patients and controls to assess the endogenous allele-specific silencing of ataxin-7 by two distinct siRNAs. We further identified altered expression of two disease-relevant transcripts in SCA7 patient cells: a twofold increase in levels of the HSP DNAJA1 and a twofold decrease in levels of the de-ubiquitinating enzyme, UCHL1. After siRNA treatment, the expression of both genes was restored towards normal levels. To our knowledge, this is the first time that allelespecific silencing of mutant ataxin-7, targeting a common SNP, has been demonstrated in patient cells. These findings highlight the advantage of an allele-specific RNAi-based therapeutic approach, and indicate the value of primary patient-derived cells as useful models for mechanistic studies and for measuring efficacy of RNAi effectors on a patient-to-patient basis in the polyQ diseases.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Allele-specific silencing of mutant Ataxin-7 in SCA7 patient-derived fibroblasts

et al. 2014

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“…Delivery of recombinant AAVs (rAAV) expressing RNAi triggers in the form of shRNAs provided clinical benefit in B05 mice after direct injection into the cerebellar cortex. 5 More recently, we showed that delivery of rAAVs expressing artificial miRNAs directed at mutant ATXN1 mRNA, to the deep cerebellar nuclei (DCN) for transport to PCs and other brainstem neurons, also improved pathologic and behavioral phenotypes in this model. 6 Similarly, rAAVs expressing microRNAs (miRNAs) directed at mutant mouse Atxn1 mRNA was beneficial when applied to the KI SCA1 model.…”

Section: Introductionmentioning

confidence: 98%

RNAi prevents and reverses phenotypes induced by mutant human ataxin‐1

Keiser

Monteys

Corbau

et al. 2016

Annals of Neurology

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Objective Spinocerebellar ataxia type 1 is an autosomal dominant fatal neurodegenerative disease caused by a polyglutamine expansion in the coding region of ATXN1. We showed previously that partial suppression of mutant ataxin-1 (ATXN1) expression, using virally-expressed RNAi triggers, could prevent disease symptoms in a transgenic mouse model and a knock in mouse model of the disease, using a single dose of virus. Here, we set out to test if RNAi triggers targeting ATXN1 could not only prevent, but also reverse disease readouts when delivered after symptom onset. Methods We administered recombinant adeno-associated virus (rAAV) expressing miS1, an artificial miRNA targeting human ATXN1 mRNA (rAAV.miS1) to a mouse model of SCA1 (B05 mice). Viruses were delivered prior to or after symptom onset at multiple doses. Control B05 mice were treated with rAAVs expressing a control artificial miRNA, or with saline. Animal behavior, molecular phenotypes, neuropathology and magnetic resonance spectroscopy were done on all groups and data were compared to wildtype littermates. Results We found that SCA1 phenotypes could be reversed by partial suppression of human mutant ATXN1 mRNA by rAAV.miS1 when delivered after symptom onset. We also identified the therapeutic range of rAAV.miS1 that could prevent or reverse disease readouts. Interpretation SCA1 disease may be reversible by RNAi therapy, and the doses required for advancing this therapy to humans are delineated.

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“…AAV.shRNA delivery mediates improvements in motor neuron function and in neuronal morphology for at least 21 weeks in murine models of degeneration in the central nervous system. 56,57 Following studies showing that AAV.shRNA delivery reduces Rhodopsin expression in vitro, 58,59 a recent report shows that in vivo expression of a human Rhodopsin transgene can be reduced by up to 90% and that a nonsilenced Rhodopsin gene can be expressed to achieve a degree of rescue. Eyes treated with the suppression-replacement construct showed some preservation of photoreceptors, indicating this approach may be useful in treating dominantly inherited retinal degenerations.…”

Section: Ocular Disease As a Target For Gene Therapymentioning

confidence: 99%

AAV-mediated gene therapy for retinal disorders: from mouse to man

2008

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A wide range of retinal disorders can potentially be treated using viral vector-mediated gene therapy. The most widely used vectors for ocular gene delivery are based on adeno-associated virus (AAV), because they elicit minimal immune responses and mediate long-term transgene expression in a variety of retinal cell types. Proof-of-concept experiments have demonstrated the efficacy of AAVmediated transgene delivery in a number of animal models of inherited and acquired retinal disorders. Following extensive preclinical evaluation in large animal models, gene therapy for one form of inherited retinal degeneration due to RPE65 deficiency is now being tested in three concurrent clinical trials. Here, we review different approaches for treating inherited retinal degenerations and more common acquired retinal disorders using AAV-based vectors.

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RNAi suppresses polyglutamine-induced neurodegeneration in a model of spinocerebellar ataxia

Cited by 621 publications

References 24 publications

Allele-specific silencing of mutant Ataxin-7 in SCA7 patient-derived fibroblasts

Allele-specific silencing of mutant Ataxin-7 in SCA7 patient-derived fibroblasts

RNAi prevents and reverses phenotypes induced by mutant human ataxin‐1

AAV-mediated gene therapy for retinal disorders: from mouse to man

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