Rational selection of small molecules that increase transcription through the GAA repeats found in Friedreich's ataxia

FEBS Lett. 2006 Oct 2;580(22):5399-405. doi: 10.1016/j.febslet.2006.09.006. Epub 2006 Sep 15.


Friedreich's ataxia (FRDA) is an autosomal recessive trinucleotide repeat disease with no effective therapy. Expanded GAA repeats in the first intron of the FRDA gene are thought to form unusual non-B DNA conformations that decrease transcription and subsequently reduce levels of the encoded protein, frataxin. Frataxin plays a crucial role in iron metabolism and detoxification. To discover small molecules that increase transcription through the GAA repeat region in FRDA, we have made stable cell lines containing a portion of expanded intron 1 fused to a GFP reporter. Small molecules identified using the competition dialysis method were found to increase FRDA-intron 1-reporter gene expression. One of these compounds, pentamidine, increases frataxin levels in patient cells. Thus our approach can be used to detect small molecules of potential therapeutic value in FRDA.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antifungal Agents / pharmacology*
  • Cells, Cultured
  • Drug Design
  • Drug Evaluation, Preclinical
  • Friedreich Ataxia / drug therapy*
  • Friedreich Ataxia / genetics
  • Friedreich Ataxia / metabolism*
  • Friedreich Ataxia / pathology
  • Genes, Reporter / drug effects
  • Genes, Reporter / genetics
  • Humans
  • Iron-Binding Proteins / biosynthesis*
  • Iron-Binding Proteins / genetics
  • Lymphocytes / metabolism
  • Lymphocytes / pathology
  • Nucleic Acid Conformation / drug effects
  • Pentamidine / analogs & derivatives
  • Pentamidine / pharmacology*
  • Transcription, Genetic / drug effects*
  • Transcription, Genetic / genetics
  • Trinucleotide Repeat Expansion / drug effects
  • Trinucleotide Repeat Expansion / genetics


  • Antifungal Agents
  • Iron-Binding Proteins
  • frataxin
  • Pentamidine