2026-08-29T14:07:58Zhttps://repisalud.isciii.es/rest/oai/request

oai:repisalud.isciii.es:20.500.12105/229192024-11-28T22:51:34Zcom_20.500.12105_15322com_20.500.12105_2051col_20.500.12105_16967

00925njm 22002777a 4500 dc Sherzai, Mursal author Valle, Adamo author Perry, Nicholas author Kalef-Ezra, Ester author Al-Mahdawi, Sahar author Pook, Mark author Virmouni, Sara Anjomani author 2020-06-05 Friedreich's ataxia (FRDA) is a progressive neurodegenerative disorder caused by a homozygous GAA repeat expansion mutation in intron 1 of the frataxin gene (FXN), which instigates reduced transcription. As a consequence, reduced levels of frataxin protein lead to mitochondrial iron accumulation, oxidative stress, and ultimately cell death; particularly in dorsal root ganglia (DRG) sensory neurons and the dentate nucleus of the cerebellum. In addition to neurological disability, FRDA is associated with cardiomyopathy, diabetes mellitus, and skeletal deformities. Currently there is no effective treatment for FRDA and patients die prematurely. Recent findings suggest that abnormal GAA expansion plays a role in histone modification, subjecting theFXNgene to heterochromatin silencing. Therefore, as an epigenetic-based therapy, we investigated the efficacy and tolerability of two histone methyltransferase (HMTase) inhibitor compounds, BIX0194 (G9a-inhibitor) and GSK126 (EZH2-inhibitor), to specifically target and reduce H3K9me2/3 and H3K27me3 levels, respectively, in FRDA fibroblasts. We show that a combination treatment of BIX0194 and GSK126, significantly increasedFXNgene expression levels and reduced the repressive histone marks. However, no increase in frataxin protein levels was observed. Nevertheless, our results are still promising and may encourage to investigate HMTase inhibitors with other synergistic epigenetic-based therapies for further preliminary studies. Sherzai M, Valle A, Perry N, Kalef-Ezra E, Al-Mahdawi S, Pook M, et al. HMTase Inhibitors as a Potential Epigenetic-Based Therapeutic Approach for Friedreich's Ataxia. Front Genet. 2020 Jun 05;11:584. 10.3389/fgene.2020.00584 1664-8021 Frontiers in Genetics http://hdl.handle.net/20.500.13003/10354 32582297 L632124054 2-s2.0-85086773977 https://hdl.handle.net/20.500.12105/22919 543120300001 FRDA Friedreich ataxia Frataxin FXN GAA repeat HMTase inhibitor HMTase Inhibitors as a Potential Epigenetic-Based Therapeutic Approach for Friedreich's Ataxia