Intrajugular VEIN DELIVERY OF AAV9-RNAi prevents neuropathological changes and weight loss in huntington's disease mice

Brett D. Dufour, Catherine A. Smith, Randall L. Clark, Timothy R. Walker, Jodi McBride

    Research output: Contribution to journalArticle

    35 Citations (Scopus)

    Abstract

    Huntington's disease (HD) is a fatal neurological disorder caused by a CAG repeat expansion in the HTT gene, which encodes a mutant huntingtin protein (mHTT). The mutation confers a toxic gain of function on huntingtin, leading to widespread neurodegeneration and inclusion formation in many brain regions. Although the hallmark symptom of HD is hyperkinesia stemming from striatal degeneration, several other brain regions are affected which cause psychiatric, cognitive, and metabolic symptoms. Additionally, mHTT expression in peripheral tissue is associated with skeletal muscle atrophy, cardiac failure, weight loss, and diabetes. We, and others, have demonstrated a prevention of motor symptoms in HD mice following direct striatal injection of adeno-associated viral vector (AAV) serotype 1 encoding an RNA interference (RNAi) construct targeting mutant HTT mRNA (mHTT). Here, we expand these efforts and demonstrate that an intrajugular vein injection of AAV serotype 9 (AAV9) expressing a mutant HTT-specific RNAi construct significantly reduced mHTT expression in multiple brain regions and peripheral tissues affected in HD. Correspondingly, this approach prevented atrophy and inclusion formation in key brain regions as well as the severe weight loss germane to HD transgenic mice. These results demonstrate that systemic delivery of AAV9-RNAi may provide more widespread clinical benefit for patients suffering from HD.

    Original languageEnglish (US)
    Pages (from-to)797-810
    Number of pages14
    JournalMolecular Therapy
    Volume22
    Issue number4
    DOIs
    StatePublished - 2014

    Fingerprint

    Huntington Disease
    RNA Interference
    Weight Loss
    Mutant Proteins
    Corpus Striatum
    Brain
    Hyperkinesis
    Neurobehavioral Manifestations
    Injections
    Muscular Atrophy
    Poisons
    Nervous System Diseases
    Transgenic Mice
    Atrophy
    Psychiatry
    Serogroup
    Veins
    Skeletal Muscle
    Heart Failure
    Messenger RNA

    ASJC Scopus subject areas

    • Molecular Biology
    • Molecular Medicine
    • Genetics
    • Drug Discovery
    • Pharmacology
    • Medicine(all)

    Cite this

    Intrajugular VEIN DELIVERY OF AAV9-RNAi prevents neuropathological changes and weight loss in huntington's disease mice. / Dufour, Brett D.; Smith, Catherine A.; Clark, Randall L.; Walker, Timothy R.; McBride, Jodi.

    In: Molecular Therapy, Vol. 22, No. 4, 2014, p. 797-810.

    Research output: Contribution to journalArticle

    Dufour, Brett D. ; Smith, Catherine A. ; Clark, Randall L. ; Walker, Timothy R. ; McBride, Jodi. / Intrajugular VEIN DELIVERY OF AAV9-RNAi prevents neuropathological changes and weight loss in huntington's disease mice. In: Molecular Therapy. 2014 ; Vol. 22, No. 4. pp. 797-810.
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