Journal article
Nonallele-specific Silencing of Mutant and Wild-type Huntingtin Demonstrates Therapeutic Efficacy in Huntington's Disease Mice
Molecular therapy, Vol.17(6), pp.1053-1063
06/2009
DOI: 10.1038/mt.2009.17
PMCID: PMC2835182
PMID: 19240687
Abstract
Huntington's disease (HD) is a fatal neurodegenerative disease caused by mutant huntingtin (htt) protein, and there are currently no effective treatments. Recently, we and others demonstrated that silencing mutant htt via RNA interference (RNAi) provides therapeutic benefit in HD mice. We have since found that silencing wild-type htt in adult mouse striatum is tolerated for at least 4 months. However, given the role of htt in various cellular processes, it remains unknown whether nonallele-specific silencing of both wild-type and mutant htt is a viable therapeutic strategy for HD. Here, we tested whether cosilencing wild-type and mutant htt provides therapeutic benefit and is tolerable in HD mice. After treatment, HD mice showed significant reductions in wild-type and mutant htt, and demonstrated improved motor coordination and survival. We performed transcriptional profiling to evaluate the effects of reducing wild-type htt in adult mouse striatum. We identified gene expression changes that are concordant with previously described roles for htt in various cellular processes. Also, several abnormally expressed transcripts associated with early-stage HD were differentially expressed in our studies, but intriguingly, those involved in neuronal function changed in opposing directions. Together, these encouraging and surprising findings support further testing of nonallele-specific RNAi therapeutics for HD.
Details
- Title: Subtitle
- Nonallele-specific Silencing of Mutant and Wild-type Huntingtin Demonstrates Therapeutic Efficacy in Huntington's Disease Mice
- Creators
- Ryan L Boudreau - Department of Internal Medicine, University of IowaJodi L McBride - Department of Internal Medicine, University of IowaInês Martins - Department of Internal Medicine, University of IowaShihao Shen - Department of Biostatistics, University of IowaYi Xing - Department of Internal Medicine, University of IowaBarrie J Carter - Targeted GeneticsBeverly L Davidson - Department of Internal Medicine, University of Iowa
- Resource Type
- Journal article
- Publication Details
- Molecular therapy, Vol.17(6), pp.1053-1063
- DOI
- 10.1038/mt.2009.17
- PMID
- 19240687
- PMCID
- PMC2835182
- NLM abbreviation
- Mol Ther
- ISSN
- 1525-0016
- eISSN
- 1525-0024
- Publisher
- Nature Publishing Group
- Language
- English
- Date published
- 06/2009
- Academic Unit
- Iowa Neuroscience Institute; Cardiovascular Medicine; Fraternal Order of Eagles Diabetes Research Center; Internal Medicine
- Record Identifier
- 9984065399602771
Metrics
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