RNA interference improves motor and neuropathological abnormalities in a Huntington's disease mouse model

Harper, Scott Q.; Staber, Patrick D.; He, Xiaohua; Eliason, Steven; Martins, Inês; Mao, Qinwen; Yang, Linda; Kotin, Robert M.; Paulson, Henry L.; Davidson, Beverly L.

doi:10.1073/pnas.0501507102

Cited by 624 publications

(497 citation statements)

References 43 publications

Supporting

Mentioning

482

Contrasting

Unclassified

Order By: Relevance

“…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%

See 1 more Smart Citation

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

et al. 2014

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2014

View full text Add to dashboard Cite

show abstract

“…Given this, the development of nucleic acid therapy by noncoding small RNAs could be an ideal approach to selectively silence mutant htt [115,116]. Harper et al [117] showed that RNA interference using adeno-associated virus-small hairpin RNA (shRNA) improves motor deficits and neuropathological phenotypes in a transgenic (N171-82Q) mouse model of HD. Most RNA interference studies using adenovirus-shRNA, lentivirus-shRNA, adeno-associated virus-miRNA, and cholesterol-conjugated siRNA have shown a reduction of mthtt aggregates, improvement of motor behavior, and reduced neuropathological sequelae (Table 1) [118][119][120][121][122][123][124][125].…”

Section: Rna Interference and Noncoding Small Rnasmentioning

confidence: 99%

Epigenetic Mechanisms of Neurodegeneration in Huntington's Disease

et al. 2013

View full text Add to dashboard Cite

Huntington's disease (HD) is an incurable and fatal hereditary neurodegenerative disorder of mid-life onset characterized by chorea, emotional distress, and progressive cognitive decline. HD is caused by an expansion of CAG repeats coding for glutamine (Q) in exon 1 of the huntingtin gene. Recent studies suggest that epigenetic modifications may play a key role in HD pathogenesis. Alterations of the epigenetic "histone code" lead to chromatin remodeling and deregulation of neuronal gene transcription that are prominently linked to HD pathogenesis. Furthermore, specific noncoding RNAs and microRNAs are associated with neuronal damage in HD. In this review, we discuss how DNA methylation, posttranslational modifications of histone, and noncoding RNA function are affected and involved in HD pathogenesis. In addition, we summarize the therapeutic effects of histone deacetylase inhibitors and DNA binding drugs on epigenetic modifications and neuropathological sequelae in HD. Our understanding of the role of these epigenetic mechanisms may lead to the identification of novel biological markers and new therapeutic targets to treat HD.

show abstract

“…Therefore, to test the shRNA knockdown approach for a more clinically relevant disease, Harper et al 27 designed an shRNA that specifically targets the transcript from a human Htt mutant allele for depletion, in a transgenic mouse model of HD. AAV2/1 vectors with U6 promoter-expressed shRNA against Huntingtin transcripts were produced and injected into the striatum and cerebellum of HD mice.…”

Section: Applications In the Central Nervous Systemmentioning

confidence: 99%

AAV vectors for RNA-based modulation of gene expression

Danos

2008

Gene Ther

View full text Add to dashboard Cite

At the post-transcriptional level, gene expression is largely regulated through a network of molecular machines that regulate pre-mRNA maturation integrity, transport, translation and degradation. These processes are based on the formation of nucleoprotein complexes and require the recognition of sequence motifs on the RNA. By masking these targets with complementary RNA sequences forming Watson-Crick base pairing, it is possible to efficiently and specifically impact on the cell phenotype, or to compensate the deleterious effect of mutations. Here we review how the adeno-associated virus technology is being exploited for expressing non-coding RNAs in tissues such as the brain, muscle or liver, in functional genomic studies as well as for the development of novel therapeutic strategies.

show abstract

RNA interference improves motor and neuropathological abnormalities in a Huntington's disease mouse model

Cited by 624 publications

References 43 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

Epigenetic Mechanisms of Neurodegeneration in Huntington's Disease

AAV vectors for RNA-based modulation of gene expression

Contact Info

Product

Resources

About