Epigenetic therapy for Friedreich ataxia

• DOI: 10.1002/ana.24260
• Publication Date: 2014-08-27T09:50:35Z
• 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
• Keywords: Frataxin; Histone deacetylase inhibitor; Vorinostat

To investigate whether a histone deacetylase inhibitor (HDACi) would be effective in an vitro model for the neurodegenerative disease Friedreich ataxia (FRDA) and to evaluate safety surrogate markers of efficacy phase I clinical trial patients.We used human FRDA neuronal cell model, derived from patient induced pluripotent stem cells, determine 2-aminobenzamide HDACi (109) as modulator FXN gene expression chromatin modifications. patients were dosed 4 cohorts, ranging 30mg/day 240mg/day formulated drug product 109, RG2833. Patients monitored adverse effects well increases mRNA, frataxin protein, modification blood cells.In 109/RG2833 mRNA levels with concomitant changes epigenetic state gene. Chromatin signatures indicate that H3 lysine 9 is key residue silencing through methylation reactivation acetylation, mediated by HDACi. Drug treatment demonstrated increased acetylation peripheral mononuclear cells. No issues encountered.Drug exposure inducing neurons comparable required see circulating lymphoid cells expression. These findings provide proof concept development therapy this fatal neurological disease.