Promoting myelin repair by targeting Wnt signalling

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The Trish MS Research Foundation is greatly honoured to have co-funded with the National Health and Medical Research Council, a National Health and Medical Research Council / MS Research Australia Betty Cuthbert Fellowship awarded to Dr David Gonsalvez, University of Melbourne. The Trish Foundation fully funded the MS Research Australia contribution.

Dr Gonsalvez has made excellent progress with investigating the Wnt/B-catenin signalling pathway and its role in production of myelin. He has successfully generated a laboratory model where this biological pathway is blocked in the cells that make myelin (oligodendrocytes) and found that myelin production is promoted when the pathway is blocked. These findings suggest that this approach could be used to promote myelin repair within a biological system.

Dr Gonsalvez then performed experiments to determine whether blocking the Wnt/B-catenin signalling pathway in oligodendrocyte precursor cells (OPCs), the cells that make oligodendrocytes, affects their production and growth. The initial findings of this have shown that OPCs continue to grow when this pathway is blocked in response to demyelination and that myelination is improved. Interestingly, OPCs also play a role in blood brain barrier maintenance and immune response. Dr Gonsalvez is investigating whether this role of OPCs may be responsible for the remyelination events observed when the Wnt/B-catenin signalling pathway is blocked. He has discovered that the immune response may be involved in the replacement of myelin once it is lost and is investigating this further.

There is evidence that an elevated level of the Wnt/B-catenin signalling pathway prevents OPCs from forming oligodendrocytes and ultimately reduces the production of myelin. Dr Gonsalvez has shown that one of the key molecules that promotes this pathway is elevated in human MS tissue. He is continuing to uncover more information about the profile of molecules involved in the Wnt/B-catenin signalling pathway that are present in human demyelinating lesions.

Uncovering the mechanism and the molecules of the Wnt/B-catenin signalling pathway involved in myelination could potentially lead to the development of new therapies that could be used to promote myelin repair and slow the progression of MS.

This work has been presented at national and international conferences and Dr Gonsalvez has won multiple travel grants to allow him to attend these scientific meetings. He has also received a multitude of grants, including from the Department of Anatomy and Neuroscience for a $10,000 microscopy lens which will allow him to accelerate his observations of the myelin repair and has received the University of Melbourne Research Support Grant for $7,800 to retrofit a microscope with equipment that will allow high power imaging of compact myelin.

This Research was generously supported by The Woodend Foundation.

Treating MS with cell and gene therapy

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Dr Natalie Payne was awarded an Incubator Grant in 2018, fully funded by the Trish MS Research Foundation, titled, “Treating MS with cell and gene therapy”.

Dr Payne and her team have created a specially designed cell that produces a drug that targets a pathway associated with the progression of MS. The drug blocks an important signal (IL-1Beta) in the immune system decreasing specific inflammation. They have shown that the drug is “inducible” meaning that the engineered cells only produce the drug when exposed to a chemical which acts as an “on” switch. Dr Payne has also shown that the drug produced from these designer cells can block the generation of T-cells, a type of immune cell that is important for generating some of the inflammation in MS. They have also developed and optimised an experimental approach to deliver their cells into organisms so that they can serve as “mini factories” pumping out high levels of drug. Using this system, they can now produce and deliver any soluble biological drug directly in the body and assess the impact on disease outcomes in laboratory models of MS.

Building on the success of this project, Dr Payne and her team have managed to secure additional funding from a Philanthropic foundation to continue this work, and we look forward to seeing this work continue.

Encouraging the natural repair abilities of immune cells

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Dr Claire McCoy was awarded an Incubator Grant in 2018, fully funded by the Trish MS Research Foundation, titled, “Encouraging the natural repair abilities of immune cells”.

Dr McCoy and her team have successfully created a laboratory model of MS in which the miR-155 is selectively absent in macrophage cells. Macrophages move in large numbers into the brain and spinal cord during the progression of MS and cause damage and demyelination to the nerve cells.

The team has assessed the effects of removing miR-155 on disease progression and severity in a laboratory model of MS. They have also assessed the effects of removing miR-155 in macrophages has had on the other cells in the immune system, and whether it influences the movement of immune cells to different parts of the body, including the number of immune cells that move into the brain and spinal cord. The results are currently under embargo while they are prepared to be written up for a scientific journal. We look forward to reporting on these results when they are published.

This work is ongoing and Dr McCoy has used data from this incubator project to successfully secure significant funding to continue this important work. She has managed to secure €1.5m from the Science Foundation Ireland.

The role of Vitamin D related genes in MS

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In 2016, Dr Lawrence Ong was awarded a Betty Cuthbert Postgraduate Scholarship co-funded by the National Health and Medical Research Council and MS Research Australia, with the MS Research Australia contribution provided with full funding support from the Trish MS Research Foundation. The Trish Foundation was honoured to be co-funding this important Research Project with the National Health and Medical Research Council.

Low blood levels of vitamin D seem to increase the risk of developing MS. Genetic studies have also shown that several of the MS risk genes are involved in the processing of vitamin D in the body. In addition, vitamin D levels appear to predict clinical activity in MS. The reasons for this are unclear, but may be linked to the effect of vitamin D on immune cells. Dr Lawrence Ong, a clinical immunologist, was awarded a Postgraduate Scholarship to look at the relationship between vitamin D and genes and the effect on immune cells. Specifically, Dr Ong was interested in whether vitamin D was turning genes on or off in immune cells using the vitamin D receptor – the vitamin D docking station found on cells – and a molecular mechanism known as methylation.

During his PhD, Dr Ong used a technique called modified reduced representation bisulfite sequencing that allowed him to analyse the methylation of all the genes present in the genome at once. As part of this work, Dr Ong also developed and optimised a bioinformatics pipeline to analyse the data specifically for this research project.

Importantly Dr Ong showed that methylation patterns on immune cells could be passed on as new immune cells are generated from stem cells to daughter cells. In further work he also looked to see whether exposure to vitamin D changed methylation patterns in immune cells taken from healthy adults. He was able to demonstrate a range of differences in the appearance of these cells as well as differences in the patterns of methylation. This forms a potential pathway by which environmental exposure to vitamin D may affect the function of immune cells and therefore the risk of MS.

Dr Ong will be continuing this work to delve deeper into the mechanisms involved. He is also interested in the relationship between another environmental risk factor for MS, the Epstein Barr Virus (EBV), and methylation patterns. He will use publicly available data to investigate this relationship. His initial comparisons of cells infected with EBV and uninfected cells that are either in a resting or activated state showed methylation differences that seemed to be independent of MS risk genes.

Dr Ong has presented his findings at a number of national and international conferences and was awarded a prize for his presentation and work at the European Academy of Allergy and Clinical Immunology conference. He is preparing a number of manuscripts for submission for publication in scientific journals and was also successful in securing further funding from MS Research Australia to continue this work through an incubator grant.

Does stimulating brain activity improve myelin repair?

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Dr Tobias Merson, Monash University Victoria, was awarded a Project Grant over 2017-2018, funded by the Trish Multiple Sclerosis Research Foundation, his Co-Investigator being Dr Stanislaw Mitew.

Dr Merson’s team have shown that increasing the electrical activity of nerve fibres in brain tissue that is not affected by MS enhances the laying down of myelin on these nerve fibres and other research has recently shown that blocking electrical activity in lesions within the MS brain reduces the brain’s ability to repair the lost myelin

In this project, Dr Merson has explored two different ways to increase the electrical activity in nerve cells and assessed what impact this increase has on the repair of myelin damage to nerve fibres in a laboratory model of MS. The first way Dr Merson and his team enhanced activity was by introducing a specific protein into the nerve cells, followed by administering a drug, this combination increased the number of electrical impulses the nerve cells produced. The second way they achieved it, was through increased physical exercise which also resulted in an increased number of electrical impulses.

Dr Merson and his team has found that increasing the electrical activity in nerve cells led to an increase in myelin density and an increase in density of myelin producing cells around the damaged nerves. Interestingly, when electrical stimulation was applied this occurred immediately in the weeks following the loss of myelin, but eventually the group which didn’t have increased electrical stimulation caught up and had similar levels of myelin density and density of myelin producing cells. These results suggest that electrical stimulation does have effect on myelination following an MS-like attack, in that it may enhance the speed in which myelin is replaced.

The success of this grant has contributed to Dr Merson successfully securing over $1 million from the National Health and Medical Research Council to expand this work and to explore how electrical stimulation might be aiding and accelerating the speed in which the myelin can be repaired in MS.

Findings attract exciting international collaborations

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The Trish Foundation is supporting a three-year MS Research Australia Project Grant awarded to A/Prof Peter Crouch who will begin preclinical trials of a therapy for progressive multiple sclerosis at The University of Melbourne. Dr Crouch’s Co-investigators are Dr James Hilton, Dr Blaine Roberts, Dr Paul Donnelly and Dr Dominic Hare.

Unfortunately, there are very limited treatment options for people with the progressive forms of disease. The development of treatments for progressive MS is hampered by the current lack of understanding of the biochemical mechanisms that differentiate relapsing-remitting MS from the progressive forms. A/Prof Crouch has discovered that copper which is normally found in the body, is not distributed normally in the body of people with progressive MS. He suggests this may affect the function of some of the body’s enzymes, leading to changes in the biochemical processes in individual cells.

In this project, A/Prof Crouch is quantifying the distribution and amount of copper in tissue from the brain and spinal cord in people with and without MS. He is also hoping to understand how copper in the body influences the molecular mechanisms that underpin progressive MS, and to begin pre-clinical trials of a potential therapy for progressive forms of the disease.

The Trish Foundation works very closely and in association with MS Research Australia. Please click here to watch MS Research Australia’s video in which A/Prof Peter Crouch and Dr James Hilton speak about their research.

In the first year of this three-year project, A/Prof Crouch and his research team have generated promising data that helps reveal the role that copper might be playing in the development of progressive MS, and its potential as a therapeutic target.

A/Prof Crouch confirms the data supports the team’s hypothesis on the involvement of copper in progressive MS. This data has come from their analysis of myelin changes in mouse models of MS-like illness. They have also been able to show preliminary data indicating that the changes in copper levels in mice respond to treatment with a copper-based drug. Their analysis of copper levels from post-mortem tissue from people with MS also supports these findings and indicates that the laboratory findings may mirror the situation in humans. This is a promising indication that the copper-based drug could eventually be taken forward for testing in people with MS.

A/Prof Crouch and his team will now continue to investigate the extent to which differences in copper levels may naturally occur in people who do not have MS, and therefore how specific their relevance is for progressive MS. They will also continue to investigate the drug treatment with the aim of optimising it for testing in MS.

These findings have been presented at a symposium in Tokyo and have attracted exciting international collaborations. The team are also preparing their initial findings for publication in a scientific journal.

What Role do Natural Killer Cells play in MS?

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The Trish MS Research Foundation has part funded an MS Research Australia Project Grant, ‘What Role do Natural Killer Cells play in MS?’, the Chief Investigator being Dr Fiona McKay, Westmead Institute for Medical Research, NSW.

Natural killer (NK) cells are responsible for killing harmful cells in the body. This includes the body’s own cells that are infected with viruses, and other immune cells that inappropriately attack our own body (autoimmune cells).

Previous work by Dr Fiona McKay and colleagues found that in some people with MS, their NK cells are not working properly. In a laboratory model of MS, they also found that malfunction of NK cells is associated with increased MS relapses.

In this Project Grant Dr McKay and her team are determining if NK cells from people with MS are able to kill cells infected with viruses, and/or autoimmune cells, in the laboratory. A number of drugs that enhance the function of NK cells have been approved to treat cancer. Dr McKay is investigating if these drugs can be repurposed to improve the function of NK cells in people with MS to kill cells infected with viruses, and/or autoimmune cells.

Dr McKay and her term have developed a test to characterise and compare different sub-types of NK cells. This technique involves passing the cells past a laser that allows them to detect over 21 different properties of the cells. This will help to reveal any differences in natural killer cells from people with and without MS.

They have also generated a system using cells grown in the laboratory in which to examine Epstein Barr Virus (EBV) infection of B cells. This virus plays an important role in the development of MS, but the exact mechanisms by which it influences susceptibility to MS remains unclear. Dr McKay and her team will use this system to see whether NK cells from people with and without MS can effectively kill B-cells that are infected with EBV and whether this might be a mechanism by which EBV plays a role in MS.

They will then use drugs to try and bolster NK cells’ abilities to kill EBV-infected cells and see whether this will improve the capacity of NK cells from people with MS to kill EBV-infected cells, or autoimmune cells.

Development of iPad Tool

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Dr Joshua Barton was awarded a Postgraduate Scholarship titled, “Subclinical disease progression and repair in multiple sclerosis: novel application of standardised functional visual biomarkers”, which was fully funded by the Trish MS Research Foundation.

The current methods available to clinicians and researchers to measure the progression of disease and disability in people with MS are relatively insensitive and must be measured over relatively long periods of time to detect changes. However, people with early MS often have changes to their brains which do not result in symptoms, so called ‘sub-clinical changes’ which can affect disability later in the disease. Clinical trials for medications that aim to slow or halt disability progression are also hampered by this lack of sensitive measures for progression.

Dr Barton, a clinician currently receiving advanced training in neurology, has undertaken a postgraduate scholarship, fully funded by the Trish MS Research Foundation, to develop a tablet based tool that will track sub-clinical changes in real-time.

In the first year of his PhD research, Dr Barton developed an iPad based tool that is able to accurately measure an individual’s function of visual contrast sensitivity. The benefit of this measure, as opposed to the traditional visual outcome measures used in clinical trials, is that the contrast sensitivity function encompasses both visual spatial sensitivity and visual contrast sensitivity. Dr Barton collaborated with the University of Sydney’s School of Information Technology to develop the iPad tool.

The iPad tool is much faster than standard testing, taking approximately two minutes per eye tested and has the added benefit of being able to be used independently by patients. This allows home-based self-testing by people with MS at a time that is convenient to them.

Dr Barton has recruited a group of people with MS to use the iPad tool to perform fortnightly self-assessments on their vision. These people will also undergo regular MRI scans to determine whether any lesions develop. This allows Dr Barton to see if the iPad tool is able to detect any lesion development which is clinically silent (doesn’t result in an obvious relapse). This work is ongoing with results to come.

Dr Barton has also recruited 50 people who are receiving the MS medication, alemtuzumab, who will use the iPad visual test to detect any visual changes. Again this tablet based testing will be tracked over time and compared with the traditional MRI and clinical measures of relapse activity and disability progression. This will help Dr Barton to identify if the tool is more sensitive to detect treatment response in comparison with the traditional measures.

During his research, Dr Barton has also developed a method for detecting the onset of the visual evoked potential (VEP). This is a measure of nerve conduction speed in the visual system and should provide a more accurate assessment of nerve speed than other techniques currently available.

Enhancing Myelin repair in multiple sclerosis

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In MS, myelin, the protective coating around the nerve cells in the brain and spinal cord is damaged by the immune system. This protective coating not only protects nerves but also provides nourishment and support, and without it nerve cells will eventually die. Current MS therapies suppress the immune system but do not promote the repair of nerve cells which have been damaged.

Professor Trevor Kilpatrick and his team are investigating a protein called Tyro3 which in the laboratory has been shown to improve the natural repair processes in the brain by causing the production of myelin. In this project, the team aimed to determine whether producing more myelin in laboratory models of MS is enough to reverse the damage associated with MS.

They also tested if certain other medications, already approved for treating other diseases, are able to promote new myelin production in the brain. Aiming to use already available medications for a new disease is known as drug re-purposing and can speed up the process of treatment approval as steps testing the safety of the medication in humans have already been carried out.

Professor Kilpatrick and his team have made considerable progress in deciphering the mechanisms of how the Tyro3 protein might be aiding in the remyelination process. This is an important step if medications targeting Tyro3 are going to be developed and used to enhance remyelination in people with MS. Although their study was only in the early stages, they have made some important findings that will inform how and when we could use any therapies aimed at activating Tyro3. They have also been focusing on parts of the brain and spinal cord which are heavily impacted by the loss of the protein Tyro3 in an effort to better understand the full role of this protein in MS. These studies could lead to the creation of new therapies or the re-purposing of current therapies approved for other diseases to enhance myelin repair, slow down or stop the progression of MS.

Enhancing brain activity to re-wrap nerve fibres

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Dr Kaylene Young, Menzies Institute for Medical Research, Tasmania, was awarded an MS Research Australia Project Grant titled, ‘Enhancing brain activity to re-wrap nerve fibres’ over 2017-2019 funded by the Trish Multiple Sclerosis Research Foundation.

Dr Young and her team have previously established that a non-invasive technique, known as repetitive transcranial magnetic stimulation, is able to massage brain activity and increase the production of cells that produce myelin in the brain. In this project, Dr Young used this technology to increase the production of myelin producing cells, to re-wrap nerve fibres in myelin and promote lesion repair in the brain in two laboratory models of MS; one model has a single small area of demyelination or damage and the other is a model of more widespread MS like disease. Dr Young is examining the brain tissue under the microscope to determine how effective this treatment is in repairing damage to the myelin coating on nerve cells and in combating disease progression in the models.

To date, Dr Young has managed to collect all brain samples needed for the study and analysis is underway. She is aiming to determine the number of new myelin producing cells within the lesion site and determine the amount and length of myelin that is generated in response to the magnetic stimulation. In the preliminary findings, Dr Young has found that in the single small lesions, the amount and length of myelin did not change in response to transcranial magnetic stimulation. However, that might be because in these cases there was already some repair underway. Dr Young is currently analysing the brain tissue which had more widespread MS like disease. Through this research, she has also determined the optimal transcranial magnetic stimulation method, which can hopefully be successfully translated to clinical trials on people with MS.

It is hoped that if these experiments are successful, the transcranial magnetic stimulation may be used as a therapy to repair existing damage in progressive MS and proceed to clinical trials.

Dr Young has received funding from the Ian Potter Foundation to purchase two new confocal microscopes that will double imaging capacity. She was also successful in receiving a collaborative National Health and Medical Research Council grant to continue to her work. She has also prepared and published several manuscripts in scientific journals.