Developing a novel drug for progressive MS

Our very generous supporters ‘dug deep’ at our 2018 Ball, enabling the Trish Foundation to fund an Incubator Grant awarded to Dr Steven Petratos.

Dr Petratos and his team have examined the levels of the thyroid hormone transporter, MCT8, during mouse development and adulthood, and how it is affected in immune cells and oligodendrocytes (the cells that make myelin) in models of demyelination. He has also investigated the levels of MCT8 in human brain tissue with neurodegenerative disorders.

Dr Petratos has shown that MCT8 levels are maintained in oligodendrocyte precursor cells (OPCs) throughout mouse development, suggesting it plays a role in their maintenance. Interestingly, its levels are substantially increased in immune cells and decreased in oligodendrocytes in the models of MS. The decreased levels of MCT8 in oligodendrocytes correlates with increased oligodendrocyte cell death during demyelination, which can be salvaged using DITPA.

Dr Petratos has also shown that thyroid hormone signalling (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.

These findings suggest that thyroid hormone transporters are necessary for cellular maintenance during brain development in laboratory models, which is altered in demyelinating conditions. They also suggest that a reduction in thyroid hormone transport into oligodendrocytes may exist in demyelinating conditions such as MS. These findings will allow Dr Petratos to benchmark current remyelination therapies against DITPA to demonstrate its effectiveness in limiting further degeneration and promoting remyelination in conditions such as progressive MS.

This work has led to an international collaboration and patent application. 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.

Dr Petratos continues to make exceptional progress (please see the article on the Research Progress page of this website titled “Potential game-changer”) and in addition to funding from the Bethlehem Griffiths Research Foundation, he was awarded a three-year Trish Translational Research Grant, fully funded by the Trish Foundation commencing 2020.

Excellent progress being achieved

The Trish Foundation is supporting a three-year Project Grant awarded to Dr Junhua Xiao, The University of Melbourne titled, “How nerve cells influence myelin repair in the brain”.

Dr Xiao has made excellent progress in the first year of the project grant. She and her team have successfully generated laboratory models where the TrkB gene has been removed from neurons (nerve cells of the brain). When these models experienced demyelination, she found that removal of TrkB in the corpus callosum (a region that connects the two hemispheres of the brain) resulted in fewer pre-existing and newly generated mature myelin producing cells, and also resulted in more precursor myelin producing cells, compared to those models that still had TrkB. In the cerebral cortex (the outer tissue of the two hemispheres of the brain), removal of TrkB did not influence the production of newly generated myelin producing cells but did reduce the amount of pre-existing mature myelin producing cells. These findings suggest that TrkB is required for the formation of mature myelin producing cells in the brain and suggest that remyelination in different regions of the brain is regulated differently.

Dr Xiao and her team are currently determining to what extent TrkB influences remyelination capacity. Following this work, she will determine how TrkB promotes remyelination. Understanding the details of myelin repair will help identify therapeutic targets to promote remyelination.

Enhancing Myelin repair in MS

The Foundation is contributing to a MS Research Australia Project Grant titled “Enhancing Myelin repair in multiple sclerosis” at the Florey Institute of Neuroscience and Mental Health, VIC, led by Professor Trevor Kilpatrick.  Co-investigators for this three-year project are Dr Simon Murray, Ms Michele Binder, Professor Bernard Zalc, Dr Junhua Xiao, Dr Anne Desmazieres and Professor Robyn McCallen.

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. In addition to focusing on the brain and spinal cord, they are also focusing on parts of the visual system, which is impacted in the absence of Tyro3. The team are currently investigating why this is the case. By understanding the full role of this protein in MS, we can better understand how targeting it may be beneficial as a treatment for 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.

The results of this study have been presented at national and international conferences, with a scientific manuscript currently in preparation.

Commencing this year, Professor Kilpatrick was awarded a Trish Translational Project Grant, fully funded by the Trish Foundation. In this innovative project, Professor Trevor Kilpatrick and his team are investigating ways to manipulate the immune system.  The cells that are being focused on are already the subject of intense study, including in early phase clinical trials for treatment of other diseases, so the work will be translatable to clinical trials in people with MS.

Developing methods to promote the creation of new myelin in MS

Following very generous support at the Trish Foundation’s 2018 Ball, an Incubator Grant was awarded to Associate Professor Anthony Don.

In the first part of his project, A/Prof Don showed in laboratory models that S1P is essential for protecting the myelinating cells of the brain against damage and that loss of myelinating cells and myelin was much more severe in the absence of S1P. He has also shown that remyelination did not occur when demyelination ceased in the absence of S1P. A/Prof Don is now determining if remyelination is permanently impeded or whether it occurs more slowly in the absence of S1P.

In the second part of his project, A/Prof Don conducted a pilot study to determine whether giving drugs that mimic S1P protect the myelinating cells and prevent severe myelin loss. He has established that the newly approved treatment for secondary progressive MS, siponimod (Mayzent), protects against the loss of myelin in a low inflammatory laboratory model of MS. This result is important as this laboratory model for MS is not dependent on the immune system’s involvement. These findings suggest that siponimod protects myelinating cells and myelin independent of its primary clinical mechanism in modulating the immune cells that play a role in MS.

These exciting results warrant further research into the role of naturally occurring S1P in protecting against the loss of neurological function in MS, and the potential for drugs mimicking S1P to promote myelin repair.

A/Prof Don has presented this work at national conferences and is currently preparing a manuscript for publication in a scientific journal. He will also be applying for Research Grants during 2020 for the Project.

A potential therapy for progressive forms of MS

Commencing 2018 the Trish Foundation began supporting a three-year MS Research Australia Project Grant awarded to Associate Professor Peter Crouch who began 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.

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 and his team have analysed myelin changes in laboratory models of MS which has supported the team’s hypothesis of the involvement of copper in progressive MS. Preliminary work has also shown that the changes in copper levels in the laboratory models responds to treatment with a copper-based drug. Their analysis of copper levels of 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 drug could eventually be taken forward for testing in people with MS.

In the second year of the project, A/Prof Crouch and his team delved deeper into the mechanisms underpinning the connection between copper and MS. They analysed the levels of genes involved in copper handling, myelin and the immune response, and determined the distribution of copper in human spinal cord tissue affected by progressive MS. They have also looked at the changes in the levels of these genes in laboratory models of MS and how these changes are impacted by treating the models with the copper drug.

This work strengthens the team’s hypothesis of the role of copper in MS, which is important should the copper drug be considered as a new treatment option for progressive MS. These findings have been presented at national and international conferences and have attracted exciting international collaborations.

A/Prof Crouch’s Project Grant was generously supported by The Woodend Foundation.

What role do natural killer cells play in MS?

The Trish Foundation contributed to a three-year MS Research Australia Project Grant awarded to Dr Fiona McKay which commenced in 2018.

Dr McKay and her team have developed a test to characterise and compare different subsets of natural killer (NK) cells. This technique involves passing the cells past a laser that allows them to detect over 21 different properties of the cells and they have used this to characterise 75 blood samples (39 samples from people with MS and 36 samples from people without MS). Dr McKay and her team have also developed a pipeline to analyse the results of this and have found that there is a subset of NK cells that are different in people with MS compared to people without MS. They are continuing to analyse the results to determine if there are more differences in NK cells between people with MS and without MS. Findings from this could potentially be used as targets for new MS treatments.

They have also generated a system using cells grown in the laboratory 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 the ability of NK cells 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.

Dr McKay and her team have also developed collaborations as a result of this work, and the findings have been presented at national and international conferences. A manuscript is currently in preparation for publication.

Using MRI to measure MS severity and progression

In 2019 Dr Justin Garber, The University of Sydney, was awarded a three-year Postgraduate Scholarship fully funded by the Trish Foundation, his Co-investigators being Professor Michael Barnett and Dr Chenyu Wang.

Dr Garber has recruited 24 participants with progressive MS for this study who have had brain MRIs performed every 6 months. At each visit, they are also having physical examinations and other physical and cognitive tests to measure their disability and rates of progression.

Dr Garber is currently developing the tools to measure changes in the participants’ MRI scans using measures of brain volume as well as tissue damage within MS lesions and outside of MS lesions. Some of these techniques will contribute to creating a map of the connections throughout the brain which can be used to measure damage caused by MS. Some refinements to the original research proposal have been made including focusing on the motor system of the brain and measuring damage of MS lesions.

Dr Garber has presented this work at several national conferences and has published several manuscripts in scientific journals.

Promoting myelin repair in the brain

Commencing 2019, Dr Simon Murray and his Co-investigator Dr Jessica Fletcher, The University of Melbourne, were awarded a two-year Project Grant fully funded by the Trish Foundation.

In the first year of his project grant, Dr Murray has established and characterised a new pre-clinical laboratory model of MS where the survival of precursor myelin producing cells is impaired, as well as their ability to form mature myelin-producing cells. This laboratory model more closely mimics what occurs in MS compared to other laboratory models.

Dr Murray is now performing experiments to determine whether the compound that mimics BDNF can repair myelin and plays a role in the growth and maturation of precursor myelin producing cells in this new laboratory model. While still in the early stages, it is hoped that this compound could potentially be a new treatment option for people with progressive MS.

Dr Murray has presented this work at an international conference.

Dr Murray’s Co-investigator, Dr Jessica Fletcher said, “Engaging with others helps us stay at the forefront of research and adapt to new findings which can change our perspective on how MS or myelin repair occurs. It’s also fulfilling to share our work with other researchers and the public through talks and presentations.”

iPad-based tool for accurate measurement

Dr Joshua Barton, Brain and Mind Centre, University of Sydney was awarded a Postgraduate Scholarship funded by the Trish Foundation, which was supervised by Professor Michael Barnett.

Dr Barton has 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. This 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 have also undergone regular MRI scans to determine whether any lesions develop. This will allow 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).

Dr Barton has also recruited 50 people who are receiving the MS medication, alemtuzumab, to use the iPad visual test to detect any visual changes. Dr Barton has tracked the participants over a two-year period to determine if there is a link between visual function measures, MRI changes and multifocal visual evoked potentials (mfVEP). MfVEP is used to measure the function of the visual pathway through the optic nerves and brain from many regions of the visual field – it should provide a more accurate assessment of nerve speed than other techniques currently available. From this part of his work, Dr Barton has determined three different ways to analyse mfVEP to extract additional information, potentially increasing the value of this clinical tool. Using these different analyses, he was able to determine differences in people whose eyes were affected by optic neuritis (a condition where the immune system attacks the nerves of the eyes) compared to those whose eyes weren’t.

Dr Barton has also performed a pilot study looking at the effect of temperature on mfVEP signals on 7 people with MS and 5 people without MS. It was conducted in conjunction with the University of Sydney’s Thermal Ergonomics Laboratory, which has previous experience in safely increasing and decreasing body temperature in people with MS. The aim of this study was to reveal nerve injury that isn’t obvious in the form of Uhthoff’s phenomenon, which is the worsening of MS symptoms as the body is overheated. Dr Barton found that people with MS had differences in mfVEPs upon heating compared to people without MS, although there wasn’t any difference between people with or without optic neuritis.

Dr Barton has presented his findings at a national conference and is preparing several scientific manuscripts for publication.

Which genes are involved in progressive MS?

Commencing 2018, Associate Professor Justin Rubio and his Co-investigators Associate Professor Stephen Leslie and Professor Michael Barnett were awarded a Project Grant funded by the Trish Foundation for two years investigating the DNA from single cells in the brain to better understand progressive MS.

A/Prof Rubio and his team have isolated and analysed DNA from nerve cells and myelin producing cells from the brain tissue of people with progressive MS. Using cutting-edge technology, the team have investigated the entire DNA content (whole genome) of 52 individual nerve cells and myelin producing cells, with a further 22 genomes underway and more to come. They are currently in the process of analysing the data using state-of-the-art computational tools tailored to analyse individual cells.

The team has discovered that nerve cells and myelin producing cells affected by MS have similar numbers of genetic mutations, but for both cell types, there is preliminary evidence suggesting that the rate of mutations is higher in tissue containing lesions than tissue not affected by lesions. The work from this project will hopefully improve our understanding of the biological processes underpinning neurodegeneration, which may pave the way for the development of targeted therapies for progressive MS.

The team is preparing to publish their results in a scientific journal and have also presented their work at a national conference. This project grant helped A/Prof Rubio leverage a further $1 million from the NHMRC to follow up this work.

A/Prof Rubio’s Research Project was generously supported by The Woodend Foundation.