title: Effect of 2'-O-methyl/thiophosphonoacetate-modified antisense oligonucleotides on huntingtin expression in patient-derived cells.
abstract: Optimizing oligonucleotides as therapeutics will require exploring how chemistry can be used to enhance their effects inside cells. To achieve this goal it will be necessary to fully explore chemical space around the native DNA/RNA framework to define the potential of diverse chemical modifications. In this report we examine the potential of thiophosphonoacetate (thioPACE)-modified 2'-O-methyl oligoribonucleotides as inhibitors of human huntingtin (HTT) expression. Inhibition occurred, but was less than with analogous locked nucleic acid (LNA)-substituted oligomers lacking the thioPACE modification. These data suggest that thioPACE oligonucleotides have the potential to control gene expression inside cells. However, advantages relative to other modifications were not demonstrated. Additional modifications are likely to be necessary to fully explore any potential advantages of thioPACE substitutions.
authors: a Department of Pharmacology; UT Southwestern Medical Center ; Dallas , TX USA.
authors: Masayuki
authors: M
authors: Matsui
authors: b Department of Chemistry and Biochemistry ; University of Colorado at Boulder ; Boulder , CO USA.
authors: Richard N
authors: RN
authors: Threlfall
authors: b Department of Chemistry and Biochemistry ; University of Colorado at Boulder ; Boulder , CO USA.
authors: Marvin H
authors: MH
authors: Caruthers
authors: a Department of Pharmacology; UT Southwestern Medical Center ; Dallas , TX USA.
authors: David R
authors: DR
authors: Corey
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004247:DNA / Q000737:chemistry; D006801:Humans; D000071058:Huntingtin Protein / Q000096:biosynthesis*; D006816:Huntington Disease / Q000188:drug therapy; D051379:Mice; D009841:Oligonucleotides / Q000737:chemistry; D016376:Oligonucleotides, Antisense / Q000737:chemistry* / Q000494:pharmacology*; D009946:Organothiophosphorus Compounds / Q000737:chemistry*; D012313:RNA / Q000737:chemistry
chemical_list: C086055:HTT protein, human; D000071058:Huntingtin Protein; D009841:Oligonucleotides; D016376:Oligonucleotides, Antisense; D009946:Organothiophosphorus Compounds; C477371:locked nucleic acid; D012313:RNA; D004247:DNA
keywords: Huntington's disease; antisense oligonucleotides; huntingtin; locked nucleic acids; phosphate modification; thiophosphonoacetate