Nonallele-specific silencing of mutant and wild-type huntingtin demonstrates therapeutic efficacy in Huntington's disease mice

Ryan L. Boudreau, Jodi L. McBride, Inês Martins, Shihao Shen, Yi Xing, Barrie J. Carter, Beverly L. Davidson

    Research output: Contribution to journalArticlepeer-review

    248 Scopus citations

    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.

    Original languageEnglish (US)
    Pages (from-to)1053-1063
    Number of pages11
    JournalMolecular Therapy
    Volume17
    Issue number6
    DOIs
    StatePublished - 2009

    ASJC Scopus subject areas

    • Molecular Medicine
    • Molecular Biology
    • Genetics
    • Pharmacology
    • Drug Discovery

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