title: Two new pimelic diphenylamide HDAC inhibitors induce sustained frataxin upregulation in cells from Friedreich's ataxia patients and in a mouse model.
abstract: BACKGROUND
  Friedreich's ataxia (FRDA), the most common recessive ataxia in Caucasians, is due to severely reduced levels of frataxin, a highly conserved protein, that result from a large GAA triplet repeat expansion within the first intron of the frataxin gene (FXN). Typical marks of heterochromatin are found near the expanded GAA repeat in FRDA patient cells and mouse models. Histone deacetylase inhibitors (HDACIs) with a pimelic diphenylamide structure and HDAC3 specificity can decondense the chromatin structure at the FXN gene and restore frataxin levels in cells from FRDA patients and in a GAA repeat based FRDA mouse model, KIKI, providing an appealing approach for FRDA therapeutics.
  
  
  RESULTS
  In an effort to further improve the pharmacological profile of pimelic diphenylamide HDACIs as potential therapeutics for FRDA, we synthesized additional compounds with this basic structure and screened them for HDAC3 specificity. We characterized two of these compounds, 136 and 109, in FRDA patients' peripheral blood lymphocytes and in the KIKI mouse model. We tested their ability to upregulate frataxin at a range of concentrations in order to determine a minimal effective dose. We then determined in both systems the duration of effect of these drugs on frataxin mRNA and protein, and on total and local histone acetylation. The effects of these compounds exceeded the time of direct exposure in both systems.
  
  
  CONCLUSIONS
  Our results support the pre-clinical development of a therapeutic approach based on pimelic diphenylamide HDACIs for FRDA and provide information for the design of future human trials of these drugs, suggesting an intermittent administration of the drug.
authors.affiliation: Laboratoire de Neurologie Expérimentale, Hôpital Erasme, Brussels, Belgium.
authors.forename: Myriam
authors.initials: M
authors.lastname: Rai
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Soragni
authors.forename: C James
authors.initials: CJ
authors.lastname: Chou
authors.forename: Glenn
authors.initials: G
authors.lastname: Barnes
authors.forename: Steve
authors.initials: S
authors.lastname: Jones
authors.forename: James R
authors.initials: JR
authors.lastname: Rusche
authors.forename: Joel M
authors.initials: JM
authors.lastname: Gottesfeld
authors.forename: Massimo
authors.initials: M
authors.lastname: Pandolfo
mesh_terms: D000818:Animals; D001483:Base Sequence; D017931:DNA Primers; D004195:Disease Models, Animal; D005621:Friedreich Ataxia / Q000235:genetics*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D033862:Iron-Binding Proteins / Q000235:genetics*; D051379:Mice; D023421:Models, Animal; D010867:Pimelic Acids / Q000494:pharmacology*; D016133:Polymerase Chain Reaction; D015854:Up-Regulation / Q000187:drug effects*; D000096923:Frataxin
chemical_list: D017931:DNA Primers; D056572:Histone Deacetylase Inhibitors; D033862:Iron-Binding Proteins; D010867:Pimelic Acids; D000096923:Frataxin