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.

INTERPRETATION:

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: Elisabetta Soragni, Wenyan Miao, Marco Iudicello, David Jacoby, Stefania De Mercanti, Marinella Clerico, Filomena Longo, Antonio Piga, Sherman Ku, Erica Campau, Jintang Du, Pablo Penalver, Myriam Rai, Joseph C Madara, Kristopher Nazor, Melinda O'Connor, Anton Maximov, Jeanne F Loring, Massimo Pandolfo, Luca Durelli, Joel M Gottesfeld, James R Rusche
• Journal: Annals of neurology (Ann Neurol) Vol. 76 Issue 4 Pg. 489-508 (Oct 2014) ISSN: 1531-8249 [Electronic] United States
• PMID: 25159818 (Publication Type: Clinical Trial, Phase I, Journal Article, Randomized Controlled Trial, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 American Neurological Association.

Chemical References

• Aminocaproates
• Benzamides
• Histone Deacetylase Inhibitors
• Iron-Binding Proteins
• Nerve Tissue Proteins
• RG2833

Topics

• Administration, Oral
• Adolescent
• Adult
• Aminocaproates (pharmacology, therapeutic use)
• Area Under Curve
• Benzamides (pharmacology, therapeutic use)
• Cell Differentiation (drug effects, genetics)
• Cell Line, Transformed
• Chromatin Immunoprecipitation
• Cohort Studies
• Cross-Sectional Studies
• DNA Methylation (drug effects, genetics)
• Dose-Response Relationship, Drug
• Double-Blind Method
• Female
• Friedreich Ataxia (drug therapy, genetics, pathology)
• Gene Expression Regulation (drug effects, genetics)
• Histone Deacetylase Inhibitors (therapeutic use)
• Humans
• Iron-Binding Proteins (genetics)
• Leukocytes, Mononuclear (drug effects, metabolism)
• Male
• Membrane Potentials (drug effects, physiology)
• Middle Aged
• Nerve Tissue Proteins (genetics, metabolism)
• Neurons (drug effects)
• Pluripotent Stem Cells
• Trinucleotide Repeat Expansion (genetics)
• Young Adult
• Frataxin