Investigating Therapeutic Effect of Different Antioxidants in Friedreich’s Ataxia (FRDA)

Friedreich’s ataxia (FRDA) is an inherited neurodegenerative disorder caused by epigenetic silencing of the frataxin gene. It is the most common inherited ataxia, affecting 1:50,000 Caucasians, and is characterised by neurodegeneration, cardiomyopathy, diabetes mellitus and skeletal deformities. There is currently no effective treatment for FRDA. However, there have been a number of recent clinical trials to investigate FRDA therapy, including the use of antioxidants, frataxin stabilisers, enhancers and replacement, iron chelators, and gene therapy. Thus far, although some positive biochemical effects have been observed in preclinical and clinical research using these disease-modifying agents, none have shown significant capacity to ameliorate the neurological symptoms associated with FRDA. Therefore, there is still a high unmet clinical need to identify a more effective FRDA therapy.

Aberrant frataxin expression in FRDA results in increased oxidative stress and mitochondrial dysfunction, driving disease progression. Recent studies in FRDA cells indicated that frataxin deficiency inhibits Nrf2 (Nuclear factor (erythroid-derived 2)-like 2 and impairs antioxidant defences, leading to elevation in lipid peroxidation. Thus, a number of experimental avenues has been pursued in order to trigger the Nrf2 antioxidant pathway and prevent lipid peroxidation. The aim of Ataxia lab is to investigate the molecular mechanisms of FRDA with the view to provide novel therapeutic strategies for FRDA diagnosis and treatment. In particular, this project will focus on investigating the therapeutic efficacy of different antioxidants to ameliorate the molecular and biochemical disease effects of FRDA using cell culture and mouse models.

References:

Anjomani Virmouni S, et al. A novel GAA-repeat-expansion-based mouse model of Friedreich's ataxia. Dis Model Mech 2015 Mar;8(3):225235.

Paupe V, et al. Impaired nuclear Nrf2 translocation undermines the oxidative stress response in Friedreich ataxia. PLoS One 2009;4(1):e4253. 

D'Oria V, et al. Frataxin deficiency leads to reduced expression and impaired translocation of NF-E2-related factor (Nrf2) in cultured motor neurons. Int J Mol Sci 2013 Apr 10;14(4):7853-7865.

Shan Y, et al. Frataxin deficiency leads to defects in expression of antioxidants and Nrf2 expression in dorsal root ganglia of the Friedreich's ataxia YG8R mouse model. Antioxid Redox Signal 2013 Nov 1;19(13):1481-1493.

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This is a self funded topic

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Meet the Supervisor(s)

Sara Anjomani Virmouni - Sara was educated at the University of Tehran, where she was awarded a Bachelor degree in animal sciences with first class honours in 2008. She moved to the Biosciences Division at Brunel University London to undertake her MSc in Molecular Medicine and Cancer Research. In 2011, Sara was awarded a scholarship by the School of Health Sciences and Social Care, Brunel University London to investigate Friedreich’s ataxia (FRDA) disease mechanisms using FRDA mouse models and cells under the supervision of Dr Mark Pook. She finished her PhD in 2013 and was awarded Vice Chancellor's best doctoral research prize. She continued her work as a Postdoctoral Research Fellow at Brunel University London to study the efficacy and tolerability of histone methyltransferase (HMTase) inhibitors in FRDA. Sara then joined the Institute of Cancer Research (ICR) as a Postdoctoral Research Fellow in 2015 to study the signaling and metabolic networks in breast cancer. In 2018, she was awarded a research grant from Friedreich’s Ataxia Research Alliance (FARA) and joined Brunel University London as a Principal Investigator to investigate the metabolic signatures of FRDA. Subsequently, she was appointed as a lecturer in Biosciences. Her research continues to investigate FRDA disease pathogenesis and therapy and identify the most effective therapy for FRDA.