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.