title: Safety of Striatal Infusion of siRNA in a Transgenic Huntington's Disease Mouse Model.
abstract: BACKGROUND
  The immune system In Huntington's disease (HD) is activated and may overreact to some therapies. RNA interference using siRNA lowers mutant huntingtin (mHTT) protein but could increase immune responses.
  
  
  OBJECTIVE
  To examine the innate immune response following siRNA infusion into the striatum of wild-type (WT) and HD transgenic (YAC128) mice.
  
  
  METHODS
  siRNAs (2'-O-methyl phosphorothioated) were infused unilaterally into striatum of four month-old WT and YAC128 mice for 28 days. Microglia number and morphology (resting (normal), activated, dystrophic), cytokine levels, and DARPP32-positive neurons were measured in striatum immediately or 14 days post-infusion. Controls included contralateral untreated striatum, and PBS and sham treated striata.
  
  
  RESULTS
  The striata of untreated YAC128 mice had significantly fewer resting microglia and more dystrophic microglia than WT mice, but no difference from WT in the proportion of activated microglia or total number of microglia. siRNA infusion increased the total number of microglia in YAC128 mice compared to PBS treated and untreated striata and increased the proportion of activated microglia in WT and YAC128 mice compared to untreated striata and sham treated groups. Cytokine levels were low and siRNA infusion resulted in only modest changes in those levels. siRNA infusion did not change the number of DARPP32-positive neurons.
  
  
  CONCLUSIONS
  Findings suggest that siRNA infusion may be a safe method for lowering mHTT levels in the striatum in young animals, since treatment does not produce a robust cytokine response or cause neurotoxicity. The potential long-term effects of a sustained increase in total and activated microglia after siRNA infusion in HD mice need to be explored.
authors.affiliation: Department of Medicine, University of Massachusetts Medical School, Worcester, MA.
authors.forename: Emily
authors.initials: E
authors.lastname: Johnson
authors.affiliation: Department of Medicine, University of Massachusetts Medical School, Worcester, MA.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Chase
authors.affiliation: Department of Medicine, University of Massachusetts Medical School, Worcester, MA.
authors.forename: Sarah
authors.initials: S
authors.lastname: McGowan
authors.affiliation: Department of Medicine, University of Massachusetts Medical School, Worcester, MA.
authors.forename: Erica
authors.initials: E
authors.lastname: Mondo
authors.affiliation: Department of Medicine, University of Massachusetts Medical School, Worcester, MA.
authors.forename: Edith
authors.initials: E
authors.lastname: Pfister
authors.affiliation: Department of Quantitative Health Sciences, University of Massachusetts Medical School, Worcester, MA.
authors.forename: Eric
authors.initials: E
authors.lastname: Mick
authors.affiliation: Department of Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA.
authors.forename: Randall H
authors.initials: RH
authors.lastname: Friedline
authors.affiliation: Department of Medicine, University of Massachusetts Medical School, Worcester, MA.|Department of Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA.
authors.forename: Jason K
authors.initials: JK
authors.lastname: Kim
authors.affiliation: Department of Massachusetts General Hospital, Charlestown, MA.
authors.forename: Ellen
authors.initials: E
authors.lastname: Sapp
authors.affiliation: Department of Massachusetts General Hospital, Charlestown, MA.
authors.forename: Marian
authors.initials: M
authors.lastname: DiFiglia
authors.affiliation: Department of Medicine, University of Massachusetts Medical School, Worcester, MA.
authors.forename: Neil
authors.initials: N
authors.lastname: Aronin
mesh_terms: D000818:Animals; D001921:Brain / Q000473:pathology*; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D006816:Huntington Disease / Q000188:drug therapy / Q000276:immunology*; D007113:Immunity, Innate / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D034741:RNA, Small Interfering / Q000276:immunology* / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D016207:Cytokines; D034741:RNA, Small Interfering
keywords: Huntington’s disease; cytokines; immune response; microglia; siRNA