title: Antisense oligonucleotide-mediated correction of transcriptional dysregulation is correlated with behavioral benefits in the YAC128 mouse model of Huntington's disease.
abstract: BACKGROUND
  Huntington's disease (HD) is a neurological disorder caused by mutations in the huntingtin (HTT) gene, the product of which leads to selective and progressive neuronal cell death in the striatum and cortex. Transcriptional dysregulation has emerged as a core pathologic feature in the CNS of human and animal models of HD. It is still unclear whether perturbations in gene expression are a consequence of the disease or importantly, contribute to the pathogenesis of HD.
  
  
  OBJECTIVE
  To examine if transcriptional dysregulation can be ameliorated with antisense oligonucleotides that reduce levels of mutant Htt and provide therapeutic benefit in the YAC128 mouse model of HD.
  
  
  METHODS
  Quantitative real-time PCR analysis was used to evaluate dysregulation of a subset of striatal genes in the YAC128 mouse model. Transcripts were then evaluated following ICV delivery of antisense oligonucleotides (ASO). Rota rod and Porsolt swim tests were used to evaluate phenotypic deficits in these mice following ASO treatment.
  
  
  RESULTS
  Transcriptional dysregulation was detected in the YAC128 mouse model and appears to progress with age. ICV delivery of ASOs directed against mutant Htt resulted in reduction in mutant Htt levels and amelioration in behavioral deficits in the YAC128 mouse model. These improvements were correlated with improvements in the levels of several dysregulated striatal transcripts.
  
  
  CONCLUSIONS
  The role of transcriptional dysregulation in the pathogenesis of Huntington's disease is not well understood, however, a wealth of evidence now strongly suggests that changes in transcriptional signatures are a prominent feature in the brains of both HD patients and animal models of the disease. Our study is the first to show that a therapeutic agent capable of improving an HD disease phenotype is concomitantly correlated with normalization of a subset of dysregulated striatal transcripts. Our data suggests that correction of these disease-altered transcripts may underlie, at least in part, the therapeutic efficacy shown associated with ASO-mediated correction of HD phenotypes and may provide a novel set of early biomarkers for evaluating future therapeutic concepts for HD.
authors: Genzyme, a Sanofi Company, Framingham, MA, USA.
authors: Lisa M
authors: LM
authors: Stanek
authors: Genzyme, a Sanofi Company, Framingham, MA, USA.
authors: Wendy
authors: W
authors: Yang
authors: Genzyme, a Sanofi Company, Framingham, MA, USA.
authors: Stuart
authors: S
authors: Angus
authors: Genzyme, a Sanofi Company, Framingham, MA, USA.
authors: Pablo S
authors: PS
authors: Sardi
authors: Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, BC, Canada.
authors: Michael R
authors: MR
authors: Hayden
authors: Isis Pharmaceuticals, Carlsbad, CA, USA.
authors: Gene H
authors: GH
authors: Hung
authors: Isis Pharmaceuticals, Carlsbad, CA, USA.
authors: C Frank
authors: CF
authors: Bennett
authors: Genzyme, a Sanofi Company, Framingham, MA, USA.
authors: Seng H
authors: SH
authors: Cheng
authors: Genzyme, a Sanofi Company, Framingham, MA, USA.
authors: Lamya S
authors: LS
authors: Shihabuddin
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D004195:Disease Models, Animal; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32 / Q000187:drug effects / Q000235:genetics; D004745:Enkephalins / Q000187:drug effects / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects*; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics*; D007041:Hypoxanthine Phosphoribosyltransferase / Q000187:drug effects / Q000235:genetics; D057967:Infusions, Intraventricular; D051379:Mice; D009048:Motor Skills / Q000187:drug effects*; D017072:Neostriatum / Q000187:drug effects* / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000187:drug effects* / Q000378:metabolism; D009687:Nuclear Proteins / Q000187:drug effects* / Q000378:metabolism; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D060888:Real-Time Polymerase Chain Reaction; D043884:Receptor, Cannabinoid, CB1 / Q000187:drug effects / Q000235:genetics; D017447:Receptors, Dopamine D1 / Q000187:drug effects / Q000235:genetics; D017448:Receptors, Dopamine D2 / Q000187:drug effects / Q000235:genetics
chemical_list: D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D004745:Enkephalins; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D016376:Oligonucleotides, Antisense; C497929:Ppp1r1b protein, mouse; D043884:Receptor, Cannabinoid, CB1; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D007041:Hypoxanthine Phosphoribosyltransferase
keywords: Antisense oligonucleotides; Huntington's disease; YAC128 mouse model; mutant huntingtin; transcriptional dysregulation