MND Australia

MND Research Australia grants awarded 2022

MND Research Australia has awarded over $3.1 million to support the best MND research commencing in 2022. MNDRA is indebted to the generosity of donors, those who leave gifts in their will, the MND&ME and MonSTaR foundations and the State MND Associations who fund this research.

The suite of grants awarded at the annual grants allocation meeting on 10 November 2021 comprises the Betty and John Laidlaw MND Research Prize for a mid-career researcher, three postdoctoral fellowships and 17 innovator grants. MNDRA has also awarded the Scott Sullivan MND Postdoctoral Fellowship, which is largely funded by MND&ME with a contribution from MNDRA, and is being offered through our funding program for the first time in 2022.

Click here for a downloadable document of all of the research funded by MNDRA in 2022. 

Research Fellowships

Lead investigator: Associate Professor Parvathi Menon
Institution: University of Sydney
Title: Improved Understanding of Brain Excitability in ALS/MND

Cortical hyperexcitability, is an important mechanism underlying MND which contributes to nerve degeneration and consequent muscle wasting, varying MND types, adverse prognosis, and disease progression. Mechanisms underlying cortical hyperexcitability in MND are partially understood and their limitation or reversal may be vital in MND management. Loss of inhibitory interneurons has been proposed as a mechanism for cortical hyperexcitability in mouse models. This research project will help prospectively interrogate the function of distinct cortical interneuron populations in sporadic MND patients using unique cortical stimulation techniques to improve understanding of this key pathogenic mechanism.

Lead investigator: Dr Fiona Bright 
Institution: Macquarie University
Title: Exploring undefined regions & novel functions of the TDP-43 protein - The molecular pursuit to uncover the cause and ultimately find a cure for MND

In 95% of MND patients, abnormal protein deposits of TDP-43 are present within cells of the brain, and spinal cord. The molecular mechanisms underlying TDP-43 pathology in MND remains unknown. The structural parts of TDP-43 containing disease-causing mutations have undergone detailed studies, yet the remaining part is significantly understudied. Importantly, this part contains TDP-43’s transport and protein binding machinery with ample opportunity to learn about its physiological movement within the brain and spinal cord. Novel regulators of TDP-43 transport, and other functions awaits discovery. This project will explore undefined regions and molecular pathways of TDP-43 which holds the key to understanding what goes wrong in MND.

Lead Investigator: Dr Mouna Haidar
Institution: Florey Institute of Neuroscience and Mental Health
Title: A novel gene therapy approach targeted to overactive brain motor neurons

There is increasing evidence that motor neurons in the brain are electrically overactive in MND, leading to damage of motor neurons in the spinal cord. We will evaluate a new gene therapy approach targeting motor neurons in the brain to reduce their overactivity in MND. Using "designer receptor" technology, we will test this approach in motor neurons grown from MND patients and mouse models. We predict that our gene therapy strategy will reduce the burden of electrical overactivity in the brain, preserving motor neurons and correcting these models, supporting future development of designer receptor therapy for MND.

Lead investigator: Dr Marnie Graco
Institution: Institute for Breathing and Sleep, VIC
Title: Optimising quality of life and survival in motor neurone disease by improving the use of overnight breathing support

Supporting breathing overnight with non-invasive ventilation improves life expectancy in motor neurone disease (MND). However only 19% of Australians living with MND currently access the treatment. This research will directly address this problem, by: 1) understanding the barriers to the uptake of non-invasive ventilation from the perspective of people living with MND, their carers / family and clinicians; 2) carefully designing a strategy that targets these barriers; and 3) implementing and testing the effectiveness of this strategy in a single Australian location. This research will optimise quality of life and survival in MND by improving the uptake of non-invasive ventilation.

Lead Investigator: Dr Fleur Garton
Institution: University of Queensland
Title: An investigation into MND biomarkers and genetic risk mechanisms to improve diagnosis/tracking and therapeutic avenues for sporadic ALS

This fellowship aims to bring together an MND research program with two key themes to address 1) new biomarkers of disease and 2) mechanisms underlying genetic risk associations. It will focus on the relatively understudied (but most common form) sporadic ALS. Potential outcomes include new methods for diagnosing and/or tracking ALS using biomarker data (alongside other biological and clinical information) and novel avenues for therapeutic intervention. By integrating clinical, molecular, and model systems and focussing on ALS cases without a known mutation (>80%), the research program will maximise the opportunity to improve the care and cure of those with MND.

Innovator Grants

Lead investigator: Dr Emma Devenney
Institution: University of Sydney, NSW
Title: Harnessing Artificial Intelligence Computer Models in MND: a novel pathway to improve patient outcomes

The systems responsible for thinking and moving work together to help us complete complex tasks. These systems may become dysfunctional early in MND and can occur before the onset of physical symptoms. This project will develop objective tests, using cutting-edge technology including Artificial Intelligence models, to accurately identify and define these features. This project will also identify the earliest brain changes that cause these symptoms. Overall, this project may lead to improvements in the diagnostic process and provide markers for progression and therapeutic effect that will improve timely access to support and care and appropriate access to pharmaceutical therapies.

Lead investigator: Dr Gabriel S. Trajano
Institution: Queensland University of Technology, QLD
Title: High-density electromyography as a new tool to monitor motor neurone changes in MND

There is a lack of biomarkers to monitor MND progression. Current methods to evaluate motor neurone changes have limited applicability because they are invasive, painful, and can only record few motor units. We propose the use of innovative non-invasive high-density electromyography to record the activity of motor units in MND patients. Our pilot data in MND patients suggests this method is feasible and could be used to determine changes in motor neurone excitability along disease progression in specific types of motor neurones. This project results will help to develop a new biomarker to track disease progression and inform clinical practice.

Lead investigator: Dr Frederik Steyn
Institute: University of Queensland, QLD
Title: Preclinical validation of macimorelin, a ghrelin mimetic, as a treatment for amyotrophic lateral sclerosis (ALS)

Not all patients with ALS are the same, and so treatments must target a range of disease processes that are relevant across patients with ALS. We will complete critical preclinical studies to show that macimorelin, an FDA approved compound with wide-ranging biological actions, can improve disease outcome in ALS. Results from this project will provide critical preclinical evidence to facilitate the rapid repurposing of macimorelin into extensive preclinical and clinical testing as a treatment for ALS.

Lead investigator: Dr Tanya McDonald
Institution: University of Queensland, QLD
Title: Investigating energy balance in the progression of MND

The body requires blood glucose concentrations to be tightly regulated to maintain health. This is mainly regulated by two hormones, glucagon and insulin. The actions of glucagon appear to be impaired in MND, and may promote disease progression. This study will use mouse models of MND and MND patients to investigate whether increasing glucagon signalling restore glucose homeostasis, and thereby slows disease progression. This will help determine whether targeting glucagon signalling is a viable therapeutic option to benefit people with MND.

Lead investigator: Dr Alison Hogan
Institution: Macquarie University, NSW
Title: RNA transport in Motor Neuron Disease - an investigation into dysfunction of the pathway and its potential for therapeutic intervention

Protein synthesis at motor neuron terminals is essential for nerve function and viability. This synthesis relies on efficient transport of molecules from the cell body to neuron terminals. Evidence indicates that the transport pathway is disrupted in MND and excitingly, that it presents a potential therapeutic target. One protein essential to the transport pathway, SFPQ, has recently been linked to MND. This study will examine SFPQ-dependent transport in motor neurons in healthy and disease conditions, with the aim of establishing its role in neurodegeneration. Our findings will provide valuable insight into the therapeutic potential of modifying the pathway in MND.

Lead investigator: Professor Julie Atkin
Institution: Macquarie University, NSW
Title: New mechanisms exploring the relationship between aging and motor neuron disease

Age is the major risk factor for MND, and ‘senescence’ is known to drive the aging process. Surprisingly, however, little is known about how senescence contributes to MND. Using disease models, our aim is to investigate whether two major mutant proteins induce senescence in MND and whether this contributes to the spread of MND throughout various cells of the nervous system. We will also examine whether existing drugs that kill senescent cells (“senolytics”) are protective in MND. These studies may identify new disease processes in MND and lead to the use of senolytic drugs as a novel treatment strategy.

Lead investigator: Dr Andrew Phipps
Institute: University of Tasmania, TAS
Title: Understanding why nerve fibres are vulnerable in MND

Axons are long processes that allow for communication between our nerve cells and muscles to enable movement. During MND, nerve cell axons breakdown, leading to loss of motor function and mortality; the mechanism of which we do not understand. In this project, we will use human nerve cells to investigate what pathways are involved in axon breakdown. By understanding why axons are vulnerable, and what pathways dysfunction during MND, we can design novel therapies to prevent axon breakdown in MND.

Lead investigator: Associate Professor Mary-Louise Rogers
Institute: Flinders University, SA
Title: Uncovering a panel of urinary proteins present in people with MND that can be used to indicate stages of disease

Our laboratory are world leaders in identifying urinary molecules that are useful as readouts for clinical trials. We now propose to use high precision mass spectrometry to uncover a panel of molecules (proteins) in urine that can be used as a measure of disease at first visit to the neurologist (prognostic marker). These molecules will also be investigated to determine if they are related to traditional clinical measurements and also to disease state. We envisage producing a panel of 50 candidate molecules that can be useful to group patients with the same disease state in future clinical trials.

Lead investigator: Dr Jessica Collins
Institution: University of Tasmania, TAS
Title: Developing blood tests to diagnose and monitor MND

This project aims to develop new blood tests for MND that can help us with one of the most challenging issues in the disease; distinguishing which nerve cells are degenerating, those in the brain or those that make up the nerves. These blood tests will help us monitor disease progression which will enable us to have a better understanding of the fundamental drivers of the disease. They will also help us understand the effects of new treatments and aid in more accurate and timely diagnoses and prognoses for people with MND.

Lead investigator: Professor Tracey Dickson
Institution: University of Tasmania, TAS
Title: Rebalancing excitability dysfunction in MND by targeting non-neuronal cells

MND has a long pre-clinical period, with dysfunction in numerous cell types and pathways converging to cause motor neuron degeneration and loss of motor function. But what keeps this dysfunction in check for so long? In this project we turn our focus to the multifaceted process of neuronal inhibition, asking what causes it to fail and trigger the onset of ALS symptoms. To answer this critical question we will determine the role of the support cells in the brain, the glia, in the onset of inhibitory network dysfunction.

Lead investigator: Dr Jeffrey Liddell
Institution: University of Melbourne, VIC
Title: How corrupted glial cells perpetrate the death of neurons

Glial cells are essential for optimal neuronal health within the central nervous system, but in MND they abandon their normal ‘neuro-supportive’ role and begin to secrete factors that cause neuronal death. We have discovered a trigger that instigates this neurotoxic conversion in MND. The work that we plan to undertake via this MNDRA Innovator Grant aims to thoroughly identify the cellular changes that occur in response to this trigger and the neurotoxic factors that the glial cells secrete. The new information generated will guide development of treatments for MND that prevent neuronal death by targeting glial cells.

Lead investigator: Professor Jacqueline Wilce
Institution: Monash University, VIC
Title: Preventing toxic protein aggregation in cells by targeting stress granules

This project investigates our newly developed TIA-1 inhibitor that has potential as a neuroprotective agent against ALS. In preliminary work we have tested the TIA-1 inhibitor in vitro and also shown that it is able to modulate stress granules (SG) in cells. SGs are subcellular structures made of protein and RNA that have been shown to trigger protein aggregation as underlies neurodegenerative disease. We anticipate that TIA-1 inhibitors will modulate SG formation, preventing the formation of neurotoxic aggregate formation. The work will provide proof-of-concept for targeting TIA-1 and potentially lead to a novel mode of intervention against ALS.

Lead investigator: Associate Professor Rebekah Ahmed
Institution: University of Sydney, NSW
Title: Sleep and autonomic function across the ALS-FTD spectrum

It is recognised that the symptoms of ALS are not limited to motor weakness, but involve other major physiological changes within the body including sleep function, and pain/somatic symptoms. These changes are potentially related to changes in the autonomic nervous system and key neural structures (hypothalamus, insula and thalamus). Using novel approaches including wearable devices, and brain imaging, the prevalence of sleep and pain symptoms in ALS and FTD will be documented, the brain structures that control these changes and at what stage of the disease these changes occur to assist in early diagnosis and development of potential treatment targets.

Lead investigator: Professor Coral Warr
Institute: La Trobe University, VIC
Title: Developing new models to help us understand the cause of variability in MND clinical presentation

Amyotrophic lateral sclerosis (ALS) shows substantial clinical heterogeneity, however what underpins this heterogeneity is not understood. In this project we will develop and use a novel in vivo animal model motor circuit, together with an established model, to test the idea that the changes in neuron excitability observed in ALS can be caused by different mechanisms, and that different changes in individual patients contribute to clinical heterogeneity. Our findings will provide important knowledge that informs future personalised treatments for ALS.

Lead investigator: Dr Shu Yang
Institution: Macquarie University, NSW
Title: Preclinical assessment of the therapeutic potential of CHCHD10 in the removal of insoluble protein

We recently discovered a new MND-linked mitochondrial protein CHCHD10 that is decreased in MND and FTD patient brains compared to individuals unaffected by the disease. Restoring these reduced levels of CHCHD10 in MND cell models decreased the amount of pathological protein aggregation usually seen in MND models and improved cell survival, possibly due to enhanced protein clearance pathways. Here we propose a preclinical study to assess whether increasing levels of CHCHD10 in the brains of an MND mouse model is beneficial in modifying disease onset and reducing disease severity and progression.

Lead investigator: Dr Lyndal Henden
Institution: Macquarie University, NSW
Title: Sex and ancestry – a recipe for gene discovery in MND

More males are affected with MND, but females have a worse prognosis. The reasons for these sex-related differences are unknown but suggest a genetic component on sex chromosomes. We aim to detect X chromosome genes that cause MND or influence disease progression by using genetic data and powerful computational tools to uncover distant ancestral relationships amongst thousands of MND cases. Integrating the largest Australian MND cohort assembled to date with global MND cases from New Zealand, United Kingdom, United States and ten European countries, this is the world’s largest MND genetics study to comprehensively investigate the X chromosome. 

Lead investigator: Dr Albert Lee
Institution: Macquarie University, NSW
Title: Using proteomics to reveal the components of protein aggregates to understand MND biology and identify potential therapeutic targets

The pathological feature of MND is the presence of protein inclusions inside motor neurons – comprising mostly of the protein TDP-43. It is still not known what other protein constituents make up these protein inclusions, and their biological role(s) in causing motor neuron degeneration. We have developed a new workflow to identify what these proteins are from various stages of MND pathology. These protein ‘signatures’ enable us to map out their cellular and biological role in MND onset and progression which will help us identify new therapeutic targets and mechanisms of toxicity to prevent TDP-43 inclusion formation.

MNDRA PhD Scholarship Top-up Grants

Lead investigator: Jeryn Chang
Institution: University of Queensland
Title: Decoding the loss of appetite and pathophysiology of the brain in motor neuron disease

The loss of appetite is observed in patients with MND. This is clinically important, as energy deficits and weight loss are associated with faster disease progression and earlier death. My studies aim to identify the impact of MND on the hypothalamus, a small area of the brain that regulates appetite, and how this may contribute to functional deficits throughout the brain. Studies aim to provide a biological basis for the loss of appetite in patients with MND, which will enhance understanding of disease, and provide insights to better manage care strategies aimed at improving quality and duration of life.

Lead investigator: Sean Keating
Institution: Queensland Brain Institute, University of Queensland
Title: TDP-43 and protein clearance in the pathogenesis and treatment of MND

In MND, toxic clumps of proteins accumulate within the brain and spinal cord, leading to neurodegeneration. Using human MND tissue, neurons grown in a dish, and genetically modified MND mice, I aim to investigate how dysfunctional cellular “waste removal” systems cause protein clumping in neurons. I also aim to discover new ways to effectively stimulate these “waste removal” systems with drugs and gene therapies, and determine whether this can increase the break-down of toxic protein clumps and protect against disease. By stopping protein clumping, we aim to extend neuron survival as a therapeutic strategy to treat people living with MND. 

Lead investigator: Katherine Lewis 
Institution: University of Melbourne
Title: Characterising Myelin Changes in Motor Neuron Disease

Despite garnering much deserved attention and funding, the primary causes underlying MND onset and progression remain elusive. This, in part, may be due to most MND research being conducted with a neuroncentric focus. We know that motor neurons are encased in a lipid-rich sheath termed myelin, which is essential for neuronal health and survival. We also know that the cells that produce the myelin have been shown to exhibit MND pathology. However, the exact role of myelin-producing cells in MND remains unclear and it is unknown to what degree their dysfunction contributes to MND onset and progression. Thus, this PhD project aims to comprehensively characterise myelin changes in MND over the course of disease, using clinically relevant mouse models, complemented with sophisticated stem cell derived ‘mini brain’ model systems. By understanding the role of myelin in MND, we can provide insight into new treatment avenues and therapeutic targets to preserve motor neuron health and function.

Lead investigator: Jianina Marallag
Institution: University of Queensland
Title: The potential role of CXCR2 activation in motor neuron disease

Excessive activation of the immune system has been found to result in motor neuron death in MND. CXCR2 is a cellular receptor that is gaining interest for its involvement in recruiting immune cells to the site of injury. Inappropriate activation of this receptor may contribute to the progression of MND. This project will utilise a drug that blocks CXCR2 in mouse models of MND and patient samples to investigate if it is able to protect motor neurons by reducing immune system activity. The results will help determine if CXCR2 can be used as a therapeutic target for MND patients.

Lead investigator: Natalie Grima
Institution: Macquarie University 
Title: Investigating novel genomic and transcriptomic features of sporadic MND

MND is marked by substantial heterogeneity and it is therefore likely that personalised therapeutic strategies will be required. However, for the 90% of patients classified as having sporadic MND, the biological factors affecting development and progression remain largely unresolved. This project aims to identify novel risk and protective factors associated with sporadic MND, providing new targets for diagnosis, research and treatment. It will employ cutting-edge genomic and transcriptomic strategies to an extensive and unique collection of patient samples to look for complex genetic variants and gene expression changes associated with disease onset and/or variable development of the hallmark TDP-43 pathology.

 

Lead investigator: Dr Anna Ridgers
Institution: Austin Health
Title: Virtual Ventilation: An evaluation of the utility of ventilator-recorded data to titrate ventilator settings in comparison to non-invasive ventilation polysomnography

Home ventilation with non-invasive ventilation (NIV) is used to support breathing in respiratory (breathing) failure due to muscle weakness in motor neuron disease. Patients require different ventilator settings to optimally support breathing and improve symptoms and survival. Settings are based on daytime assessment, with subsequent overnight laboratory sleep study and face to face appointments. This is important for successful NIV but can be burdensome for patients and their carers. Newer generations of NIV record information that clinicians can review remotely. This study aims to assess whether remotely recorded ventilator data could be used to optimise ventilator settings without having to rely upon a hospital sleep study, providing the scientific foundation for remote, patient centred models of care.

Lead investigator: Courtney Clark
Institution: University of Tasmania
Title: Inhibitory Regulation of Motor Neurons: A new target mechanisms for MND

Currently there are few treatments available to motor neuron disease patients, which provide substantial improvement in lifespan and quality of life. Previously therapies have focused on improving motor neuron pathology. However, in amyotrophic lateral sclerosis (ALS), inhibitory network activity which is vital for supporting motor neuron function is dysfunctional. Through the use of mouse models and induced-motor neurons, interneurons and glia derived from patient cells, this project aims to understand how inhibitory interneurons can be used as a therapy to improve motor neuron health in ALS.

 

Lead investigator: Laura Reale
Institution: University of Tasmania
Title: Can we stop the spread of TDP-43 pathology in ALS?

ALS is caused by a destruction of neurons that are part of the motor system in the brain and spinal cord. It is not known how disease moves through this system and we have few effective treatments to stop the spread. In my PhD, I aim to discover why one population of neurons can make another population stop working, ie, how the disease spreads, and test a non-invasive intervention to stop this destruction from spreading. If we can better understand why the whole system fails and how to protect against this, then we can develop new effective treatments for ALS.

Currently funded multiyear grants from previous years

Lead investigator: Associate Professor Yazi Ke
Institution: Macquarie University 
Title: Novel therapeutic strategies targeting TDP-43 in Motor Neuron Disease

Our research team has discovered a new, previously unidentified protein complex that appears to be involved in Motor Neurone Disease (MND). This protein complex contributes to disease processes such as nerve cell death. This proposal has three main aims: firstly, to understand how different components of this protein complex contribute to its function; secondly, to study this protein complex in an established MND mouse model to understand its disease-relevance; and, finally, to harness the knowledge of this protein complex in the development of two highly feasible therapeutic approaches in a pre-clinical setting. This project could identify new therapies for MND.

Lead Investigator: Dr Emily McCann
Institution: Macquarie University 
Title: Investigating the role of complex genomic variation in MND

Gene mutations are the only known cause of MND, however almost 90% of patients have an unidentified genetic cause of MND. Little is also known about why the clinical presentation of MND varies substantially between patients. In this project, I will use innovative bioinformatic strategies to search through the genomes of MND patients to find complex genomic changes that play a role in the cause, onset and progression of MND. Once identified, these MND-relevant genomic changes will provide clues to how MND develops and progresses, to help patients and clinicians make informed decisions about treatment and family management strategies.

Lead investigator: Dr Thomas Shaw
Institution: University of Queensland
Title: Ultra-High Field MRI of Spinal Cord Tissue in Motor Neurone Diseases

Characterising differences in MND sub-types including ALS and PLS is important for understanding the disease. This project aims to distinguish these sub-types, which have separate patterns of brain and spine pathology. To achieve this, I will use Magnetic Resonance Imaging to measure tissue properties of brain and spine over time in MND patients, comparing these with clinical outcomes of disease. The project will generate significant outcomes by - for the first time - relating pathology in the brain and spinal cord to MND sub-types over time. This will increase understanding of mechanisms accounting for the irreversible progression of MND.

Lead investigator: Dr Nicholas Geraghty 
Institution: University of Wollongong
Title: High-throughput flow cytometry drug screen to discover new treatments for MND

Motor Neurone Disease (MND) arises due to proteins misfolding inside motor neurone cells, leading to toxicity, cell death and loss of motor function. TDP-43 is an important protein known to misfold, leading to its clumping or “aggregating”, which causes cell death and leads to MND. This project uses a cell model in which TDP-43 forms toxic aggregates, in a high-throughput drug screen of thousands of chemicals to find potential drugs to treat MND patients. A small number of “hits” have already been identified and will be screened in animal models of MND, to identify a therapeutic to treat MND patients.

Lead investigator: Dr Mehdi van den Bos
Institution: Westmead Hospital, NSW
Title: Deep learning as a tool to advance the diagnosis and pathophysiological understanding of ALS

ALS can be a difficult disease to diagnose and is proving even more challenging to cure. Increasingly we are realising that early intervention is needed and there are many signs brain overactivity is an early driving cause of the disease. This fellowship proposes to use advanced neurophysiological methods (probing brain function with magnetic brain stimulation and brain wave recordings) together with artificial intelligence (the technique of deep learning) to make possible early diagnosis, improve our understanding of the drivers of the disease in patients and find a reliable biological marker to accelerate drug trials that will deliver a cure.
 

Lead investigator: Dr Luke McAlary
Institution: University of Wollongong, NSW
Title: Targeting Prion-Like Strains of TDP-43

Toxic proteins in MND are capable of spreading from cell to cell in the spinal cord and brain by recruiting normal healthy protein. This spread is controlled by the shape of the toxic protein, some shapes spread more readily than others. Advanced imaging technologies have been produced where we can see the shape of individual proteins. We plan to use these imaging technologies to define the shape(s) of toxic MND proteins and apply a broad set of drug discovery methods to identify the best drugs to target them.