Dr Marguerite Evans-Galea

Biography:

Dr Marguerite Evans-Galea leads international collaborations to understand disease mechanism and develop novel therapies and biomarkers for repeat-associated neurodegenerative diseases.

The primary focus of her research program is to develop cell and gene therapies and identify therapeutic targets for Friedreich ataxia. She has received Young Investigator Awards from the Friedreich Ataxia Research Alliance, USA and the Australasian Gene and Cell Therapy Society. She has also received travel awards to present her research internationally.

With experience on multiple institute, government and educational committees, Dr Evans-Galea regularly peer reviews for international journals and funding bodies, and currently serves on two editorial boards. She also serves on the Immune Responses Committee of the American Society for Gene and Cell Therapy, the executive committee of the Australasian Gene and Cell Therapy Society and the executive of the Australian Science and Innovation Forum, a partner of the Australian Academy of Technological Sciences and Engineering.

Committed to empowering early career researchers and women in science, Dr Evans-Galea has enjoyed supervising students and fellows in Australia and the USA. She was founding Chair of the Early-Mid Career Researcher Forum with the Australian Academy of Science and is currently a steering committee member of the Science in Australia Gender Equity Forum and co-founder of Women in Science AUSTRALIA.

A strong advocate for science, Dr Evans-Galea has led multiple policy submissions, met with Members of Parliament, presented at Australian Parliament House and convened national meetings. Dr Evans-Galea regularly communicates on science-related topics via social and mainstream media.

Other Affiliations:

Honorary Fellow, Department of Paediatrics, The University of Melbourne

Awards:

2015 - Travel Award, International Ataxia Research Conference, UK
2014 - First Prize, Health Hack for Medical Research
2013 - Australian Leadership Award
2012 - Travel Award, Ataxia Investigators Meeting, National Ataxia Foundation USA
2012 - Travel Award, Theo Murphy High Flyers Think Tank, Australian Academy of Science
2010 - Leadership Award, Murdoch Children's Research Institute
2009 - New Investigator Award, Friedreich Ataxia Research Alliance, USA
2009 - Panos Ioannou Young Investigator Award, Australasian Gene and Cell Therapy Society
2006 - Travel Award, American Society of Gene and Cell Therapy, USA

Research:

Friedreich ataxia is the most common inherited ataxia and usually begins in childhood. It causes progressive damage to the nervous system and wide-ranging symptoms, including unsteadiness. Ultimately, affected individuals will require a wheelchair. In most individuals, Friedreich ataxia also affects the heart, with increased thickness of the heart wall (cardiomyopathy) and irregular heart rhythms (arrhythmia). In Friedreich ataxia, the altered gene is called FXN and this instructs cells to make the frataxin protein. A DNA expansion in FXN means people with Friedreich ataxia have lower levels of frataxin compared to unaffected individuals.

Why is this important?

Individuals with Friedreich ataxia experience impaired quality of life and can live for decades with a severe disability. The associated human and healthcare costs are significant. More than 300 Australian children and young adults live with Friedreich ataxia; with another 10,000 in the USA and Europe. Our goal is to understand disease mechanism and develop safe, effective therapies for Friedreich ataxia that readily translate to the clinic.

Projects:

Developing cell and gene therapy for Friedreich ataxia
This project aims to develop an effective treatment for Friedreich ataxia by introducing new genetic material into cells to increase frataxin – a process called gene therapy. This project uses inactivated viruses as 'Trojan horses' to deliver frataxin to Friedreich ataxia models. The overall goal is to develop safe and effective autologous gene therapy for Friedreich ataxia. Ultimately, restoring function to even a small percentage of cells could positively affect the microenvironment and improve overall outcome.

Investigating epigenetic changes in Friedreich ataxia to understand disease mechanism, identify novel therapeutic targets and develop therapies
This project investigates the epigenetic changes in Friedreich ataxia to understand the role epigenetic disruption plays in modulating disease outcome. In Friedreich ataxia, disease-causing DNA expansions undergo epigenetic changes that lead to FXN silencing. These changes include repressive histone modifications and differential DNA methylation. Our team observed a characteristic pattern of DNA methylation surrounding the DNA expansion in cells from individuals with Friedreich ataxia (e.g. blood). We and others have shown changes in DNA methylation relates independently to the expansion size and age of onset. We also showed DNA methylation can predict FXN expression, and this expression inversely correlates with disease severity. The exact role of DNA methylation changes in FRDA disease pathogenesis is not fully understood, but clearly a disease-specific DNA methylation pattern is present in individuals with Friedreich ataxia. Our vision is to identify novel therapeutic targets and develop safe compounds to increase frataxin for testing in well-characterized disease models, and ultimately in clinical trials for Friedreich ataxia.

Disease-causing mutations in Friedreich ataxia: insights from frataxin
The majority of individuals with Friedreich ataxia are homozygous for trinucleotide repeat expansions, with the remainder compound heterozygous for an expansion and a point/insertion/deletion DNA mutation in FXN. We have previously identified a novel deletion-insertion mutation of FXN in two siblings with a severe Friedreich ataxia phenotype. To date, there have been no reports of individuals with Friedreich ataxia homozygous for point mutations in FXN. In this project, we use the structure of human frataxin to develop three-dimensional models of mutant frataxin, and examine the impact of disease-causing mutations on protein function and clinical outcome in Friedreich ataxia.

Galea CA, Huq A, Lockhart PJ, Tai G, Corben LA, Yiu EM, Gurrin LC, Lynch DR, Gelbard S, Durr A, Pousset F, Parkinson M, Labrum R, Giunti P, Perlman SL, Delatycki MB * and Evans-Galea MV *. (2015) Compound heterozygous FXN mutations and clinical outcome in Friedreich ataxia. Ann Neurol. in press doi: 10.1002/ana.24595.

Yiu EM, Tai G, Peverill RE, Lee KJ, Croft KD, Mori TA, Scheiber-Mojdehkar B, Sturm B, Praschberger M, Vogel AP, Rance G, Stephenson SEM, Sarsero JP, Stockley C, Lee CYJ, Churchyard A, Evans-Galea MV, Ryan MM, Lockhart PJ, Corben LA and Delatycki MB. (2015) An open-label trial in Friedreich ataxia suggests clinical benefit with high-dose resveratrol, without effect on frataxin levels. J Neurol 262:1344-53

Evans-Galea MV *, Pébay A, Dottori M, Corben LA, Ong SH, Lockhart PJ and Delatycki MB. (2014) Cell and gene therapy for Friedreichataxia: progress to date. Hum Gene Ther 25:684-93

Evans-Galea MV *, Lockhart PJ, Galea CA, Hannan AJ and Delatycki MB. (2014) Beyond loss of frataxin: the complex molecularpathology of Friedreich ataxia. Discovery Med 17:25-35

Delatycki MB, Tai G, Corben LA, Yiu EM, Evans-Galea MV, Stephenson SEM, Gurrin L, Allen KJ, Lynch DR and Lockhart PJ. (2014) HFE p.C282Y heterozygosity is associated with earlier disease onset in Friedreich ataxia. Mov Disord 29:940-3

Evans-Galea MV *, Hannan AJ, Carrodus N, Delatycki MB and Saffery R. (2013) Epigenetic modifications in trinucleotide repeat diseases. Trends Mol Med 19:655-663

Evans-Galea MV *, Carrodus N, Rowley SM, Corben LA, Tai G, Saffery R, Galati J, Wong NC, Craig JM, Lynch DR, Regner S, Brocht AFD, Perlman SL, Bushara KO, Gomez CM, Wilmot GR, Li L, Varley E, Delatycki MB and Sarsero JP. (2012) FXN methylation predicts expression and clinical outcome in Friedreich ataxia. Annals Neurol 71:487-497 ¥

¥ article was highlighted in Nature Reviews Neurol

Corben LA, Georgiou-Karistianis N, Bradshaw JL, Evans-Galea MV, Churchyard AJ and Delatycki MB. (2012) Characterising the neuropathology and neurobehavioural phenotype in Friedreich ataxia: A systematic review. Adv Exp Med Biol. 769:169-84

Evans-Galea MV, Corben LA, Hasell J, Galea CA, Fahey MC, du Sart D and Delatycki MB. (2011) A novel deletion-insertion mutation identified in exon 3 of FXN in two siblings with a severe Friedreich ataxia phenotype. Neurogenetics 12:307-313

Liu J, Verma PJ, Evans-Galea MV, Delatycki MB, Michalska A, Leung J, Crombie D, Sarsero JP, Williamson R, Dottori M and Pébay A. (2011) Generation and function of induced-pluripotent stemcell lines from Friedreich ataxia patients. Stem Cell Rev & Rep 7:703-713

*corresponding author

Funding:

Funding
1. Project Grant, National Health and Medical Research Council (NHMRC), Australia; Chief Investigator B, 2013-2015
2. New Investigator Project Grant, Friedreich Ataxia Research Alliance, USA; Principal Investigator 2009-2011
3. Project Grant, Friedreich Ataxia Research Association, Australasia; Principal Investigator, 2009-2011
4. Project Grant, Australian Rotary Health Research Fund, Australia; Principal Investigator, 2009-2011
5. Project Grant, Collier Charitable Fund, Australia; Principal Investigator, 2011
6. Project Grant, Friedreich Ataxia Research Association, Australasia; Co-Investigator, 2009-2010

Acknowledgement
To all who support this research in the Bruce Lefroy Centre for Genetic Health Research at the Murdoch Childrens Research Institute through generous donations, volunteering and/or ethically approved participation in these projects - thank you.

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