Entry for:The Peer Prize for Women in Science
1. Summary of your research (150 words max)
We live in a time of innovation and discovery, yet a frontier that remains is our ability to treat diseases of the brain. Motor neurone disease (MND), also known as amyotrophic lateral sclerosis (ALS), is a relentless neurological disorder that robs a person of the neurons that control voluntary movement. The loss of these neurons results in progressive paralysis and death, and we are yet to develop a cure.
Our capacity to treat disorders such as MND is limited by our knowledge of the processes that lead to that disease. By adopting a Bedside to Bench to Bedside approach to research, I have increased our capacity to generate a greater understanding of the impact that altered energy metabolism has on the progression of MND. By engaging with MND patients, clinical experts, and basic researchers, I have adopted an integrated research approach to achieve a world free of MND.
2. Describe your approach and broader findings (500 words max)
Motor neurone disease (MND) is a devastating neurological disorder that strips people of their capacity to interact with the world. MND locks people in their bodies until they die from respiratory failure or associated complications, usually within 27 months of diagnosis. Clearly, there is an urgent need to develop strategies to treat this disease.
The Bedside to Bench to Bedside approach
To accelerate our capacity to find a cure or treatment for MND, we must develop innovative and integrative approaches that evolve from previous successes. Research strategies that are based on bench to bedside translation have provided significant breakthroughs to treat disease. In MND, however, this has not been the case. Indeed, the only compound that provides limited benefits in MND was first developed at the bedside, tested at the bench, and then brought back to the bedside as a treatment.
In 2014 I initiated a Bedside to Bench to Bedside initiative, forming a multidisciplinary research program that integrates neurologists, clinical researchers, stem cell researchers, neuroscientists, physiologists, and biomedical researchers across multiple research centres. The vision was to develop comprehensive and innovative screening platforms that would facilitate the identification of novel mechanisms that could be targeted to improve the quality of life and to extend the survival of people living with MND. Integral to this vision was the implementation of a patient-directed research agenda. The Bedside to Bench to Bedside approach allows us to focus on the needs of each individual patient, and it will enhance our capacity to develop tailored treatments for MND.
Our studies in patients with MND have allowed us to investigate whether an inability to maintain metabolic homeostasis may impact a patient’s quality of life, while accelerating the rate of disease progression. Our results confirm that the metabolic needs of some MND patients are greatly increased, and that changes in whole-body energy metabolism may worsen their disease symptoms. In translating this knowledge from the bedside to the bench, we have identified defects in the processes that regulate energy metabolism in the brain and muscle of preclinical models of MND. I am now focussed on investigating the pathways that control energy metabolism in neurons and muscle that have been derived from MND patient induced pluripotent stem cells. As part of these studies I will test compounds that target metabolic flux in these neurons and muscle, with the specific goal of improving energy metabolism to sustain their function and survival. Ultimately, the translation of positive research findings in human-derived cells from the bench back to the bedside will expedite clinical trials for MND.
3. What is the wider contribution or impact to your scientific field(s)? (300 words max)
An increase in the incidence of age-associated neurodegenerative diseases is placing an increasing burden on global health expenditure. Given the complexity of the brain, current treatments for neurodegenerative diseases are largely limited by the multifactorial nature of these diseases and the difficulties associated with identifying viable treatment targets. By adopting the Bedside to Bench to Bedside approach, my goal is to deliver the discoveries of today that will lead to the personalised treatments of tomorrow.
More broadly, my research into the impact of altered energy metabolism on the onset and progression of MND has implications for all neurodegenerative disorders. There are an increasing number of studies that highlight the co-existence of neurodegenerative disorders (including Parkinson’s disease, Huntington’s disease, Alzheimer’s disease, and dementia) and altered metabolic homeostasis. Thus, it is plausible that defects in the processes that regulate metabolic flux may underpin or exacerbate neurological symptoms. By defining how changes in metabolic homeostasis contribute to the aetiology of neurodegenerative disease, we will identify the relationships between energy balance and neurodegeneration. This knowledge will allow us to determine whether accommodating for dysregulated metabolic homeostasis provides a promising strategy for the management of all major neurodegenerative diseases. Ultimately, this will support a healthier ageing population, which will in turn mitigate the pressures associated with increased health spending on age-associated brain diseases.
4. Potential ideas you would like to explore to take this research further? (300 words max)
Clinical trials aim to validate treatments that have the potential to improve disease outcomes. Due to the heterogeneous nature of MND, the success of clinical trials in this area has been slowed, and it is increasingly evident that an umbrella approach to treating this disease may not be an option. If we are to embrace a future of personalised medicine in MND, we must first develop a means to allow the successful completion of personalised clinical trials.
My future research will explore approaches that will assist us in identifying patients who would benefit most from specific clinical treatments, and to conduct clinical trials aimed at addressing individual needs. To achieve this goal I must establish our current patient-screening platform at multiple assessment centres across the globe. I am currently engaging with research teams in the Netherlands (where we are conducting a sister study), and hope to expand our studies to include clinical centres across Australia, Europe and America. Once our preclinical studies have identified suitable drug candidates, it is anticipated that we will have the means to identify individuals who will benefit from these treatments, and thus the capacity to direct trials to meet the needs of individuals with similar disease traits.
5. Please share a link for researchers to access your article, data-set or thesis
More information about this work can be found at https://www.uq.edu.au/sbms/staff/shyuan-ngo
Data on the patient screening platform is currently being prepared for publication and assessment for IP protection.