title: Sustained effects of nonallele-specific Huntingtin silencing.
abstract: OBJECTIVE
  Huntington's disease (HD) is a fatal autosomal dominant neurodegenerative disorder caused by a polyglutamine expansion in the huntingtin (htt) protein. No cure is available to date to alleviate neurodegeneration. Recent studies have demonstrated that RNA interference represents a promising approach for the treatment of autosomal dominant disorders. But whether an allele-specific silencing of mutant htt or a nonallele-specific silencing should be considered has not been addressed.
  
  
  METHODS
  We developed small hairpin RNA targeting mutant or wild-type htt transcripts, or both.
  
  
  RESULTS
  We confirmed the therapeutic potential of sihtt administered with lentiviral vectors in rodent models of HD and showed that initiation of small interfering RNA treatment after the onset of HD symptoms is still efficacious and reduces the HD-like pathology. We then addressed the question of the impact of nonallele-specific silencing and demonstrated that silencing of endogenous htt to 25 to 35% in vivo is altering several pathways associated with known htt functions but is not inducing overt toxicity or increasing striatal vulnerability up to 9 months after treatment.
  
  
  CONCLUSIONS
  These data indicate that the coincident silencing of the wild-type and mutant htt may be considered as a therapeutic tool for HD.
authors.affiliation: Commissariat à l'Energie Atomique, Institute of Biomedical Imaging (I2BM) and Molecular Imaging Research Center, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Drouet
authors.forename: Valérie
authors.initials: V
authors.lastname: Perrin
authors.forename: Raymonde
authors.initials: R
authors.lastname: Hassig
authors.forename: Noëlle
authors.initials: N
authors.lastname: Dufour
authors.forename: Gwennaelle
authors.initials: G
authors.lastname: Auregan
authors.forename: Sandro
authors.initials: S
authors.lastname: Alves
authors.forename: Gilles
authors.initials: G
authors.lastname: Bonvento
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Brouillet
authors.forename: Ruth
authors.initials: R
authors.lastname: Luthi-Carter
authors.forename: Philippe
authors.initials: P
authors.lastname: Hantraye
authors.forename: Nicole
authors.initials: N
authors.lastname: Déglon