Nonallele-specific Silencing of Mutant and Wild-type Huntingtin Demonstrates Therapeutic Efficacy in Huntington's Disease Mice

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...

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Bibliographic Details
Published in:Molecular therapy 2009-06, Vol.17 (6), p.1053-1063
Main Authors: Boudreau, Ryan L, McBride, Jodi L, Martins, Inês, Shen, Shihao, Xing, Yi, Carter, Barrie J, Davidson, Beverly L
Format: Article
Language:English
Subjects:
Animals
Blotting, Northern
Blotting, Western
Cell Line
Gene expression
Gene Expression Regulation - genetics
Gene Silencing - physiology
Gene therapy
Humans
Huntingtin Protein
Huntington Disease - genetics
Huntington Disease - metabolism
Huntington Disease - therapy
Huntingtons disease
Immunohistochemistry
Internal medicine
Mice
Mice, Inbred C57BL
MicroRNAs
MicroRNAs - genetics
MicroRNAs - physiology
Nerve Tissue Proteins - genetics
Nerve Tissue Proteins - metabolism
Neurons
Neurotoxicity
Nuclear Proteins - genetics
Nuclear Proteins - metabolism
Oligonucleotide Array Sequence Analysis
Original
Plasmids
Polymerase Chain Reaction
Proteins
RNA, Small Interfering - genetics
RNA, Small Interfering - physiology
Toxicity
Vectors (Biology)
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Summary: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.
ISSN:1525-0016
1525-0024
DOI:10.1038/mt.2009.17