Activating frataxin expression by single-stranded siRNAs targeting the GAA repeat expansion

Xiulong Shen, Audrius Kilikevicius, Daniel O'Reilly, Thazha P. Prakash, Masad J. Damha, Frank Rigo, David R. Corey

Research output: Contribution to journalArticlepeer-review

13 Scopus citations


Friedreich's ataxia (FRDA) is an incurable neurodegenerative disorder caused by reduced expression of the mitochondrial protein frataxin (FXN). The genetic cause of the disease is an expanded GAA repeat within the FXN gene. Agents that increase expression of FXN protein are a potential approach to therapy. We previously described anti-trinucleotide GAA duplex RNAs (dsRNAs) and antisense oligonucleotides (ASOs) that activate FXN protein expression in multiple patient derived cell lines. Here we test two distinct series of compounds for their ability to increase FXN expression. ASOs with butane linkers showed low potency, which is consistent with the low T m values and suggesting that flexible conformation impairs activity. By contrast, single-stranded siRNAs (ss-siRNAs) that combine the strengths of dsRNA and ASO approaches had nanomolar potencies. ss-siRNAs provide an additional option for developing nucleic acid therapeutics to treat FRDA.

Original languageEnglish (US)
Pages (from-to)2850-2855
Number of pages6
JournalBioorganic and Medicinal Chemistry Letters
Issue number17
StatePublished - Sep 15 2018


  • Antisense oligonucleotides
  • Frataxin
  • Friedreich's ataxia
  • Gene activation
  • ss-siRNAs

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry


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