Use this URL to cite or link to this record in EThOS:
Title: Investigating novel therapies for Friedreich's ataxia
Author: Sherzai, Mursal
ISNI:       0000 0004 7658 7661
Awarding Body: Brunel University London
Current Institution: Brunel University
Date of Award: 2018
Availability of Full Text:
Access from EThOS:
Access from Institution:
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 transcriptional issues. 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 the FXN gene to heterochromatin silencing. Therefore, as an epigenetic-based therapy, I 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 human and mouse primary fibroblasts. We show that a combination treatment of BIX0194 and GSK126, significantly increased FXN gene expression levels and reduced the repressive histone marks. However, no increase in frataxin expression was seen. Nevertheless, our results are still promising and may encourage to investigate HMTase inhibitors with other synergistic epigenetic-based therapies for further preliminary studies. Additionally, it has been reported that ubiquitin-proteasome pathway (UPP) controls frataxin stability, thus leading to the development of new therapeutic approaches aimed at preventing the degradation of frataxin. Here we investigated the efficacy of various proteasome inhibitors (MG132, Bortezomib, Salinosporamide A and Ixazomib) using human primary fibroblasts. Only treatments using ixazomib indicated a small increase in frataxin protein; II however, an increase in the cell cycle stress modulator, p27Kip1, was also observed. Therefore, at this stage the use of proteasome inhibitor compounds cannot be advocated for FRDA therapy. Moreover, a study has proposed that increased degradation of D-serine by D-amino acid oxidase (DAO), may lead to low NMDA functioning and impair neural signalling, causing ataxia. Therefore, we investigated a DAO inhibitor, TAK-831, on the YG8sR FRDA mouse model, and detected a significant improvement in ataxia motor coordination deficits. TAK 831 is now proposed for further studies and is currently undergoing randomized Phase 2 clinical trials for FRDA in USA.
Supervisor: Pook, M. ; Rudolph, C. Sponsor: Takeda Pharmaceutical Limited Cambridge
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Epigenetics ; Proteasome inhibitors ; HMTase inhibitors