title: Hydrophobically Modified siRNAs Silence Huntingtin mRNA in Primary Neurons and Mouse Brain.
abstract: Applications of RNA interference for neuroscience research have been limited by a lack of simple and efficient methods to deliver oligonucleotides to primary neurons in culture and to the brain. Here, we show that primary neurons rapidly internalize hydrophobically modified siRNAs (hsiRNAs) added directly to the culture medium without lipid formulation. We identify functional hsiRNAs targeting the mRNA of huntingtin, the mutation of which is responsible for Huntington's disease, and show that direct uptake in neurons induces potent and specific silencing in vitro. Moreover, a single injection of unformulated hsiRNA into mouse brain silences Htt mRNA with minimal neuronal toxicity. Thus, hsiRNAs embody a class of therapeutic oligonucleotides that enable simple and straightforward functional studies of genes involved in neuronal biology and neurodegenerative disorders in a native biological context.
authors.affiliation: RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, Massachusetts, USA.|Department of Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Julia F
authors.initials: JF
authors.lastname: Alterman
authors.affiliation: Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Lauren M
authors.initials: LM
authors.lastname: Hall
authors.affiliation: RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, Massachusetts, USA.|Department of Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Coles
authors.affiliation: RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, Massachusetts, USA.|Department of Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Hassler
authors.affiliation: RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, Massachusetts, USA.|Department of Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Marie-Cecile
authors.initials: MC
authors.lastname: Didiot
authors.affiliation: Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Chase
authors.affiliation: RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Jasmin
authors.initials: J
authors.lastname: Abraham
authors.affiliation: Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Emily
authors.initials: E
authors.lastname: Sottosanti
authors.affiliation: Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Emily
authors.initials: E
authors.lastname: Johnson
authors.affiliation: Department of Neurology, Mass General Institute for Neurodegenerative Disease, Charlestown, Massachusetts, USA.
authors.forename: Ellen
authors.initials: E
authors.lastname: Sapp
authors.affiliation: RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, Massachusetts, USA.|Department of Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Maire F
authors.initials: MF
authors.lastname: Osborn
authors.affiliation: Department of Neurology, Mass General Institute for Neurodegenerative Disease, Charlestown, Massachusetts, USA.
authors.forename: Marian
authors.initials: M
authors.lastname: Difiglia
authors.affiliation: Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Neil
authors.initials: N
authors.lastname: Aronin
authors.affiliation: RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, Massachusetts, USA.|Department of Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Anastasia
authors.initials: A
authors.lastname: Khvorova