Professor Martin Delatycki, Dr. Roger Peverill, Dr. Louise Corben & A/Professor Michael Cheung (Melbourne) and Dr. David Lynch, Dr. Kimberly Lin & Dr. Victor Ferrari (Philadelphia)
The goal of this study is to provide vital information regarding the nature of heart involvement in Friedreich ataxia and to identify the best techniques for testing promising therapeutics. Increased thickness of the heart walls is a common feature in Friedreich ataxia, and is a predictor of symptomatic heart disease and premature mortality. This increase in wall thickness is likely to involve both loss of heart muscle cells and an increase in scar tissue. To examine this, the investigators are using a new cardiac magnetic resonance imaging (CMR) technique that shows promise in detecting early scarring in the heart muscle wall. They are also studying the relationship between heart changes in Friedreich ataxia and one of the body’s natural hormonal systems (the renin-angiotensin-aldosterone system), which is known to play a role in other types of heart disease. Additionally, they are measuring a number of blood markers of heart function in individuals with and without FRDA, in order to understand the mechanisms that may contribute to the heart muscle changes. These biomarkers have the potential to be highly beneficial in future Friedreich ataxia clinical trials. (This project is co-funded with the Friedreich’s Ataxia Research Alliance.)
Dr. Louise Corben, Murdoch Children’s Research Institute, University of Melbourne
While motor dysfunction is the hallmark of Friedreich Ataxia, there is evidence that some degree of cognitive impairment is part of the gross symptomatology. This project aims to translate the understanding of the neurobehavioural profile associated with Friedreich ataxia into intervention that results in improved function. Advanced clinical and neuroimaging methods will be used to determine the efficacy of intervention in 1) cognitive and 2) motor (upper limb) dysfunction in individuals with FRDA.
Studies include evaluation and analysis of neurological and functional MRI measures, cardiac function, gait, speech, vision and ocular motility, hearing acuity, quality of life and sexual function in individuals with Friedreich ataxia.
This comprehensive clinical research program is one of the sites of the Collaborative Clinical Research Network in Friedreich’s Ataxia (CCRN in FA), which is an international network of clinical research groups working together to advance treatments and clinical care. The network collaborates with pharmaceutical companies, government agencies, other research groups and the patient community to facilitate clinical research and trials needed to identify new therapies.
Enormous advances in stem cell technology over the past few years have established methods to generate embryonic-like cells from adult human tissue. These cells are known as induced pluripotent stem cells (iPSCs) and they have essentially the same properties as embryonic stem cells, which means they can be differentiated into any mature cell type. Thus, (for example) skin cells obtained from an individual can be changed into neurons or cardiac cells.
Ongoing research at the University of Melbourne by Dr. Alice Pébay (Centre for Eye Research Australia) and Dr. Mirella Dottori (Centre for Neural Engineering) suggests the possibility that transplanting these cells and the tissue engineered from them could become an effective therapy for Friedreich ataxia. A major advantage is that these transplanted cells and tissue would not be rejected because they are obtained from the individual receiving the transplant.
Working together, Dr. Pébay and Dr. Dottori generated and characterized iPSCs from Friedreich ataxia patients, and they successfully differentiated these cells into neurons and cardiomyocytes. This landmark study, which was published in 2011, pointed out the value of these neuronal and cardiac cells as models of direct relevance to understanding the pathophysiology of Friedreich ataxia and for studying the efficacy of promising treatments for neurodegeneration and cardiomyopathy in Friedreich ataxia. (http://www.ncbi.nlm.nih.gov/pubmed/21181307)
Both Dr. Dottori and Dr. Pébay are continuing their studies of iPSCs from Friedreich ataxia patients: Dr. Dottori with iPSC-derived neurons and Dr. Pébay with the cardiac cells differentiated from iPSCs
In a study published in 2014, Dr. Dottori’s group found that while neurons differentiated from Friedreich ataxia iPSCs had relatively low levels of frataxin as expected, their mitochondrial function was not abnormal. And they demonstrated that these Friedreich ataxia neural progenitor cells integrate into the nervous system and differentiate into neuronal and glial lineages when transplanted in the cerebellar regions of host adult rodents. This is exciting because it means that these Friedreich ataxia iPSC-derived neural progenitors have the capacity to differentiate, survive and integrate into the adult nervous system. (http://www.ncbi.nlm.nih.gov/pubmed/25000412).
Dr. Dottori and her colleagues have now developed and published an efficient system to differentiate iPSCs to a very specific type of neuron, the peripheral sensory neurons of the dorsal root ganglia (DRG), which is highly relevant for Friedreich ataxia. (http://www.ncbi.nlm.nih.gov/pubmed/25753817), Their next step will be generating Friedreich ataxia iPSC-derived sensory DRG neural progenitors and transplanting them into the DRG regions of adult and neonatal rodents. The results of these studies will provide valuable information regarding the possibility of using this approach as an effective treatment for neurodegeneration in Friedreich ataxia.
In 2013, Dr. Pébay and her colleagues published their exciting work demonstrating that iPSC-derived cardiomyocytes can be used to engineer functional cardiac muscle tissue. Not only does this provide tissue for studying the pathophysiology of cardiac disease and for drug discovery and testing in Friedreich ataxia, it could lead to generating cardiac grafts that can replace damaged myocardium. (http://www.ncbi.nlm.nih.gov/pubmed/23884641).
Dr. Pébay is now working on establishing a heart-specific profile in Friedreich ataxia iPSC-derived cardiomyocytes and developing a drug-screening platform using these cells, which will be of enormous benefit for testing promising new treatments for cardiomyopathy in Friedreich ataxia.