Effect of 2'-O-methyl/thiophosphonoacetate-modified antisense oligonucleotides on huntingtin expression in patient-derived cells

Masayuki Matsui, Richard N. Threlfall, Marvin H. Caruthers, David R. Corey

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)e1146391
JournalArtificial DNA, PNA & XNA
Volume5
Issue number3
DOIs
StatePublished - Dec 15 2014

Keywords

  • antisense oligonucleotides
  • huntingtin
  • Huntington's disease
  • locked nucleic acids
  • phosphate modification
  • thiophosphonoacetate

ASJC Scopus subject areas

  • Biochemistry
  • Organic Chemistry

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