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.

Do genetic changes in the brain have a role to play in progressive MS?

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MS is a very varied disease, and the course an individual person’s disease will take cannot currently be predicted. It is unclear what factors are responsible for the transition to progressive disease. While large genetic studies have identified over 200 genes involved in the risk of developing relapsing remitting MS, similar studies in progressive MS have not found risk genes that contribute to the transition to progressive forms of MS.

Associate Professor Rubio is examining the DNA and genes of individual brain cells of people with MS. This is because not all cells in our bodies are the same. Despite cells starting off containing the same DNA, individual cells can develop genetic mutations as we age. These mutations in individual cells may influence the way those cells act and function. Associate Professor Rubio is investigating if mutations in individual brain cells in people with MS might be responsible for the development of progressive MS.

In this project, Associate Professor Rubio and his team are isolating single cells from the post-mortem brain tissue of people who had MS during their life. Using a process called Next Generation Sequencing, his team are studying the DNA of these cells.

Associate Professor Rubio and his team have isolated and analysed DNA from nerve cells and cells that are responsible for making myelin, called oligodendrocytes from the MS brain tissue. Using cutting-edge technology, the team have isolated and investigated all the DNA content (also known as the entire genome) from the cells of 6 people with MS, 3 more than initially planned.

In doing this work, the team have also made cutting-edge improvements to the methodology for studying the DNA. These technical developments will have flow on effects to increase the efficiency and accuracy of this research to study the DNA changes that might contribute to disability progression in MS as well benefiting other similar fields of research.

While additional results from this study are currently being analysed, the researcher has identified that some of the same genetic (somatic) mutations exist in both types of cells, nerve cells and oligodendrocytes, studied from the brain of a person with MS. This highlights the possibility that a specific biological mechanism may underpin the risk of progressive MS. These are early results that need further investigation, but this could help reveal targets for the development of new medications to prevent disease progression.

The researchers are preparing a paper on their results so far for publication and have presented their work at a national conference.

Development of a new drug to overcome progressive MS

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In 2018 the Trish Foundation partnered with MS Research Australia to fully fund additional research of Dr Steven Petratos, Monash University. Dr Petratos was awarded a one year Project Grant to test a drug that could stop and potentially reverse progressive MS.

The damage to the myelin layer in MS not only hinders the nerve impulses travelling down the nerve fibres, but also leaves the cells vulnerable to dying. It is thought that this nerve death is a large contributor to progressive MS. Dr Petratos and his team have previously generated strong data indicating that a protein called MCT8, a thyroid hormone transporter, is vital for the survival of oligodendrocytes, the myelin producing cells. They have also developed a drug called DITPA, which can mimic the activity of the MCT8 protein. This project sets out to conduct further laboratory tests of this potential new treatment for progressive MS, by investigating this drug as a way of promoting remyelination and protection of nerve cells. The team ultimately hopes to take this drug forward for testing in clinical trials in people with MS.

Dr Petratos and his team have investigated the levels of the MCT8 protein in cells of the body during development and adulthood, and in laboratory models of demyelination. They have also investigated the level of MCT8 protein in human brain tissue with neurodegenerative disorders. Their results show that this protein is present throughout development in the cells that lead to oligodendrocytes suggesting it is important for their survival. Interestingly, following injury, which could result in demyelination, the protein level of MCT8 increased in immune cells and decreased in myelin producing cells.

Dr Petratos has also shown that thyroid hormone signaling (a chemical system by which cells communicate with each other) is reduced in the models of demyelination and altered in human brain tissue with neurodegenerative disorders. While more analysis of these findings is required, they suggest that proteins like MCT8 are necessary during brain development, and that their levels in cells are altered following damage to myelin. Dr Petratos is currently in the process of testing the drug, DITPA, in laboratory models of MS. These findings may provide a new platform for investigation of novel interventions to limit further degeneration and promote remyelination in conditions such as progressive MS.

Dr Petratos has presented his research at national conferences and has received further funding from the Bethlehem Griffiths Research Foundation. He has also prepared and published several manuscripts in scientific journals.

Promoting myelin repair by targeting Wnt signalling

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In 2016, Dr David Gonsalvez was awarded a Betty Cuthbert Fellowship 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.

Current treatments for MS are focused on stopping the immune system from damaging the myelin, and this respite from the immune attack can allow some natural regrowth of myelin. However, none of these therapies directly promote myelin repair.

In older lesions, myelin repair is, in fact, inhibited by the scarring and general conditions in the lesion. Dr Gonsalvez has been investigating a particular signalling pathway (a chemical system by which cells communicate with each other) that is thought to inhibit myelin repair called the Wnt/B-catenin signalling pathway. He is interested in how this signalling affects the cells which produce myelin and determine whether blocking these signals will then promote myelin repair. This work has the potential to identify new therapeutic targets that promote myelin regrowth and slow the progression of MS.

Dr Gonsalvez has successfully generated a laboratory model where this chemical signal is specifically blocked in oligodendrocytes (the cells that make myelin) and found that this promoted the generation of myelin. This finding suggests that this approach could be used to promote myelin repair within a person.

Dr Gonsalvez has shown that Wnt/B-catenin chemical signalling is more active in human MS tissue, and this may ultimately prevent some of the cells that make myelin. These chemicals could also play a role in the immune system and maintaining the blood brain barrier. While examining their effects, Dr Gonsalvez has discovered that the immune response may be involved in the remyelination events. He is now in the process of finding out how this is contributing to remyelination.

This work has been presented at national and international conferences and Dr Gonsalvez has won multiple travel grants which will allow him to attend these scientific meetings. He is preparing a number of manuscripts for publication in scientific journals.