Journal article
Preclinical Safety of RNAi-Mediated HTT Suppression in the Rhesus Macaque as a Potential Therapy for Huntington's Disease
Molecular therapy, Vol.19(12), pp.2152-2162
12/2011
DOI: 10.1038/mt.2011.219
PMCID: PMC3242667
PMID: 22031240
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.
Details
- Title: Subtitle
- Preclinical Safety of RNAi-Mediated HTT Suppression in the Rhesus Macaque as a Potential Therapy for Huntington's Disease
- Creators
- Jodi L McBride - , Beaverton, OregonMark R Pitzer - , Beaverton, OregonRyan L Boudreau - , Iowa City, IowaBrett Dufour - , Beaverton, OregonTheodore Hobbs - , Iowa City, IowaSergio R Ojeda - , Beaverton, OregonBeverly L Davidson - , Iowa City, Iowa
- Resource Type
- Journal article
- Publication Details
- Molecular therapy, Vol.19(12), pp.2152-2162
- Publisher
- Nature Publishing Group
- DOI
- 10.1038/mt.2011.219
- PMID
- 22031240
- PMCID
- PMC3242667
- ISSN
- 1525-0016
- eISSN
- 1525-0024
- Alternative title
- Safety of HTT Suppression in the Macaque Brain
- Language
- English
- Date published
- 12/2011
- Academic Unit
- Iowa Neuroscience Institute; Cardiovascular Medicine; Fraternal Order of Eagles Diabetes Research Center; Internal Medicine
- Record Identifier
- 9984065389002771
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