Preclinical safety of RNAi-mediated HTT suppression in the rhesus macaque as a potential therapy for Huntington's disease

Jodi McBride, Mark R. Pitzer, Ryan L. Boudreau, Brett Dufour, Theodore Hobbs, Sergio Ojeda, Beverly L. Davidson

    Research output: Contribution to journalArticle

    133 Citations (Scopus)

    Abstract

    To date, a therapy for Huntington's disease (HD), a genetic, neurodegenerative disorder, remains elusive. HD is characterized by cell loss in the basal ganglia, with particular damage to the putamen, an area of the brain responsible for initiating and refining motor movements. Consequently, patients exhibit a hyperkinetic movement disorder. RNA interference (RNAi) offers therapeutic potential for this disorder by reducing the expression of HTT, the disease-causing gene. We have previously demonstrated that partial suppression of both wild-type and mutant HTT in the striatum prevents behavioral and neuropathological abnormalities in rodent models of HD. However, given the role of HTT in various cellular processes, it remains unknown whether a partial suppression of both alleles will be safe in mammals whose neurophysiology, basal ganglia anatomy, and behavioral repertoire more closely resembles that of a human. Here, we investigate whether a partial reduction of HTT in the normal non-human primate putamen is safe. We demonstrate that a 45% reduction of rhesus HTT expression in the mid- and caudal putamen does not induce motor deficits, neuronal degeneration, astrogliosis, or an immune response. Together, these data suggest that partial suppression of wild-type HTT expression is well tolerated in the primate putamen and further supports RNAi as a therapy for HD.

    Original languageEnglish (US)
    Pages (from-to)2152-2162
    Number of pages11
    JournalMolecular Therapy
    Volume19
    Issue number12
    DOIs
    StatePublished - Dec 2011

    Fingerprint

    Putamen
    Huntington Disease
    RNA Interference
    Macaca mulatta
    Safety
    Basal Ganglia
    Primates
    Hyperkinesis
    Neurophysiology
    Inborn Genetic Diseases
    Movement Disorders
    Therapeutics
    Neurodegenerative Diseases
    Mammals
    Rodentia
    Anatomy
    Alleles
    Brain
    Genes

    ASJC Scopus subject areas

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

    Cite this

    Preclinical safety of RNAi-mediated HTT suppression in the rhesus macaque as a potential therapy for Huntington's disease. / McBride, Jodi; Pitzer, Mark R.; Boudreau, Ryan L.; Dufour, Brett; Hobbs, Theodore; Ojeda, Sergio; Davidson, Beverly L.

    In: Molecular Therapy, Vol. 19, No. 12, 12.2011, p. 2152-2162.

    Research output: Contribution to journalArticle

    McBride, Jodi ; Pitzer, Mark R. ; Boudreau, Ryan L. ; Dufour, Brett ; Hobbs, Theodore ; Ojeda, Sergio ; Davidson, Beverly L. / Preclinical safety of RNAi-mediated HTT suppression in the rhesus macaque as a potential therapy for Huntington's disease. In: Molecular Therapy. 2011 ; Vol. 19, No. 12. pp. 2152-2162.
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