Activation of frataxin protein expression by antisense oligonucleotides targeting the mutant expanded repeat

Liande Li, Xiulong Shen, Zhongtian Liu, Michaela Norrbom, Thazha P. Prakash, Daniel O'Reilly, Vivek K. Sharma, Masad J. Damha, Jonathan K. Watts, Frank Rigo, David R. Corey

Research output: Contribution to journalArticlepeer-review

31 Scopus citations


Friedreich's Ataxia (FA) is an inherited neurologic disorder caused by an expanded GAA repeat within intron 1 of the frataxin (FXN) gene that reduces expression of FXN protein. Agents that increase expression of FXN have the potential to alleviate the disease. We previously reported that duplex RNAs (dsRNAs) and antisense oligonucleotides (ASOs) complementary to the GAA repeat could enhance expression of FXN protein. We now explore the potential of a diverse group of chemically modified dsRNAs and ASOs to define the breadth of repeat-targeted synthetic nucleic acids as a platform for therapeutic development for FA. ASOs and dsRNAs can activate FXN protein expression in FA patient-derived cell lines that possess varied numbers of GAA repeats. Increased FXN protein expression was achieved by ASOs incorporating diverse chemical modifications with low nanomolar potencies, suggesting substantial flexibility in choosing compounds for further chemical optimization and animal studies. Our data encourage further development of ASOs as agents to treat FA.

Original languageEnglish (US)
Pages (from-to)23-33
Number of pages11
JournalNucleic Acid Therapeutics
Issue number1
StatePublished - Feb 2018


  • Friedreich's ataxia
  • antisense oligonucleotide
  • frataxin
  • gene activation

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Drug Discovery


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