title: Intrajugular vein delivery of AAV9-RNAi prevents neuropathological changes and weight loss in Huntington's disease mice.
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.
authors.affiliation: 1] Department of Behavioral Neuroscience, Oregon Health and Science University, Portland, Oregon, USA [2] Division of Neuroscience, Oregon National Primate Research Center, Beaverton, Oregon, USA.
authors.forename: Brett D
authors.initials: BD
authors.lastname: Dufour
authors.affiliation: Division of Neuroscience, Oregon National Primate Research Center, Beaverton, Oregon, USA.
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Smith
authors.affiliation: Division of Neuroscience, Oregon National Primate Research Center, Beaverton, Oregon, USA.
authors.forename: Randall L
authors.initials: RL
authors.lastname: Clark
authors.affiliation: Division of Neuroscience, Oregon National Primate Research Center, Beaverton, Oregon, USA.
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Walker
authors.affiliation: 1] Department of Behavioral Neuroscience, Oregon Health and Science University, Portland, Oregon, USA [2] Division of Neuroscience, Oregon National Primate Research Center, Beaverton, Oregon, USA [3] Department of Neurology, Oregon Health and Science University, Portland, Oregon, USA.
authors.forename: Jodi L
authors.initials: JL
authors.lastname: McBride
mesh_terms: D000818:Animals; D000229:Dependovirus; D004195:Disease Models, Animal; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000008:administration & dosage; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D007601:Jugular Veins; D051379:Mice; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D034622:RNA Interference; D015431:Weight Loss / Q000235:genetics
chemical_list: C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins