title: Epigenetic therapy for Friedreich ataxia.
abstract: OBJECTIVE
  To investigate whether a histone deacetylase inhibitor (HDACi) would be effective in an in vitro model for the neurodegenerative disease Friedreich ataxia (FRDA) and to evaluate safety and surrogate markers of efficacy in a phase I clinical trial in patients.
  
  
  METHODS
  We used a human FRDA neuronal cell model, derived from patient induced pluripotent stem cells, to determine the efficacy of a 2-aminobenzamide HDACi (109) as a modulator of FXN gene expression and chromatin histone modifications. FRDA patients were dosed in 4 cohorts, ranging from 30mg/day to 240mg/day of the formulated drug product of HDACi 109, RG2833. Patients were monitored for adverse effects as well as for increases in FXN mRNA, frataxin protein, and chromatin modification in blood cells.
  
  
  RESULTS
  In the neuronal cell model, HDACi 109/RG2833 increases FXN mRNA levels and frataxin protein, with concomitant changes in the epigenetic state of the gene. Chromatin signatures indicate that histone H3 lysine 9 is a key residue for gene silencing through methylation and reactivation through acetylation, mediated by the HDACi. Drug treatment in FRDA patients demonstrated increased FXN mRNA and H3 lysine 9 acetylation in peripheral blood mononuclear cells. No safety issues were encountered.
  
  
  CONCLUSIONS
  Drug exposure inducing epigenetic changes in neurons in vitro is comparable to the exposure required in patients to see epigenetic changes in circulating lymphoid cells and increases in gene expression. These findings provide a proof of concept for the development of an epigenetic therapy for this fatal neurological disease.
authors.affiliation: Departments of Cell and Molecular Biology, Scripps Research Institute, La Jolla, CA.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Soragni
authors.forename: Wenyan
authors.initials: W
authors.lastname: Miao
authors.forename: Marco
authors.initials: M
authors.lastname: Iudicello
authors.forename: David
authors.initials: D
authors.lastname: Jacoby
authors.forename: Stefania
authors.initials: S
authors.lastname: De Mercanti
authors.forename: Marinella
authors.initials: M
authors.lastname: Clerico
authors.forename: Filomena
authors.initials: F
authors.lastname: Longo
authors.forename: Antonio
authors.initials: A
authors.lastname: Piga
authors.forename: Sherman
authors.initials: S
authors.lastname: Ku
authors.forename: Erica
authors.initials: E
authors.lastname: Campau
authors.forename: Jintang
authors.initials: J
authors.lastname: Du
authors.forename: Pablo
authors.initials: P
authors.lastname: Penalver
authors.forename: Myriam
authors.initials: M
authors.lastname: Rai
authors.forename: Joseph C
authors.initials: JC
authors.lastname: Madara
authors.forename: Kristopher
authors.initials: K
authors.lastname: Nazor
authors.forename: Melinda
authors.initials: M
authors.lastname: O'Connor
authors.forename: Anton
authors.initials: A
authors.lastname: Maximov
authors.forename: Jeanne F
authors.initials: JF
authors.lastname: Loring
authors.forename: Massimo
authors.initials: M
authors.lastname: Pandolfo
authors.forename: Luca
authors.initials: L
authors.lastname: Durelli
authors.forename: Joel M
authors.initials: JM
authors.lastname: Gottesfeld
authors.forename: James R
authors.initials: JR
authors.lastname: Rusche
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000614:Aminocaproates / Q000494:pharmacology / Q000627:therapeutic use; D019540:Area Under Curve; D001549:Benzamides / Q000494:pharmacology / Q000627:therapeutic use; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D002461:Cell Line, Transformed; D047369:Chromatin Immunoprecipitation; D015331:Cohort Studies; D003430:Cross-Sectional Studies; D019175:DNA Methylation / Q000187:drug effects / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D005621:Friedreich Ataxia / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000235:genetics; D056572:Histone Deacetylase Inhibitors / Q000627:therapeutic use*; D006801:Humans; D033862:Iron-Binding Proteins / Q000235:genetics*; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000187:drug effects; D039904:Pluripotent Stem Cells; D019680:Trinucleotide Repeat Expansion / Q000235:genetics; D055815:Young Adult; D000096923:Frataxin
chemical_list: D000614:Aminocaproates; D001549:Benzamides; D056572:Histone Deacetylase Inhibitors; D033862:Iron-Binding Proteins; D009419:Nerve Tissue Proteins; D000096923:Frataxin; C000593436:RG2833