Role for EBV in MS

As a result of very generous support received at the Trish MS Winter Wonderland Ball, Stephen Schibeci was awarded an Incubator Grant titled, “How the EBV transcription factor EBNA2 regulates MS risk”, in lay terms, “A gene from a common virus changes the risk of Multiple Sclerosis”.

The Incubator Grant looks at whether the Epstein-Barr virus affects the risk of multiple sclerosis through interaction with MS risk genes.

Genetic changes have been identified which may pre-dispose an individual to MS, but genetic change is
insufficient to result in disease. An environmental cue is necessary in addition to any specific genetic change. Epstein-Barr virus (EBV) infection has been implicated as one possible environmental cue, but the mechanism for this involvement is unclear. We have found that a gene from EBV alters the expression of five MS risk genes and that inhibition of this EBV gene prevents this alteration in expression of these risk genes. This viral gene can be targeted (silenced) in such a way that the expression risk genes of MS can be reduced and, with new techniques on the horizon, symptoms of MS may be reduced or eliminated completely. The evidence for a role of EBV as an environmental cue and its link to genetic make-up of the individual in the development of MS is now stronger.

The studies also provide further insights into poorly understood mechanisms through which
environmental factors including viruses can interact with human genetic factors to alter human
disease. The role for EBV in MS is now more than just inference.

A new collaboration has arisen from this work, with results pointing to a number of avenues for studies in the next 12 months. Future studies have been initiated with Dr Chantelle Ahlenstiel at the Kirby Institute, University of NSW. The results have supported her siRNA approach to silencing Epstein-Barr virus. By targeting key genes including EBNA2 we can take advantage of her “block-and-lock” approach as a therapeutic option for EBV in relapsing-remitting MS. The design of suitable siRNA reagents by the Ahlenstiel lab can be tested with the assays used in this work.

With the completion of the research aims of this Incubator Grant, the results from these experiments have confirmed a role for Epstein-Barr virus in the development of MS and, in particular, how a transcription factor of this virus drives the disease process.

Strength to strength

The Trish MS Research Foundation funded the important work, ‘Enhancing brain activity to re-wrap nerve fibres’ of Associate Professor Kaylene Young at the Menzies Institute for Medical Research, Tasmania in 2017-2019.

A/Prof Young’s inspiring research has gone from strength to strength.

A/Prof Young, along with Professor Bruce Taylor at the Menzies Institute of Medical Research, was awarded the MS Research Australia-Macquarie Group Foundation Paired Fellowship. This Paired Fellowship links together the work of a researcher and clinician in the field of MS.

In her laboratory research, Associate Professor Young found that a form of non-invasive transcranial magnetic stimulation can promote myelin growth in laboratory models of MS. A/Prof Young and Professor Taylor are continuing to work on the pre-clinical and clinical studies of non-invasive transcranial magnetic stimulation to promote myelin growth.

One of the aims of the Fellowship is to progress the work undertaken by A/Prof Young in this project and proceed to clinical trials to ultimately treat people with progressive forms of MS. A clinical trial has been launched to determine if the treatment is safe and effective for people with MS.

The progress that has been made on these studies is huge and exciting and we look forward to the outcomes. Other laboratory studies conducted as part of this Fellowship investigated the genetics of MS and how they impact myelin-producing cells in the brain. These lines of investigation will hopefully underpin the development of new treatments for people with progressive forms of MS.”

The Trish MS Research Foundation is proud to have earlier made a contribution to this very encouraging research.

PrevANZ Update

The Trish MS Research Foundation contributed $200,000 to the world-first vitamin D MS Prevention Trial, PrevANZ.

This study aims to see whether vitamin D supplementation can delay the onset of MS. In this gold standard double-blind placebo-controlled trial, people who had experienced their first MS-like episode and were diagnosed with CIS (clinically isolated syndrome) were recruited. They were then randomised into different groups, given either a mock treatment (placebo) or different doses of vitamin D and then observed for 12 months.

202 people were enrolled in the trial, and the last participant has just finished the 12-month observation period. Statisticians and clinicians are now busy compiling the results, and we look forward to the release of the results in Mid-2021.

A team of clinicians and researchers from Australia and New Zealand, with expertise in MS neurology, MS clinical trials, endocrinology and epidemiology was assembled to oversee the trial. The trial has been coordinated by MS Research Australia, with contributions from the MS Society of WA, the Trish MS Research Foundation, MS Queensland, Foundation 5 Million+, the John T Reid Trust and the MS Society of Tasmania.

Incubator grant makes its mark

Following very generous support at the Trish Foundation’s 2018 Ball, an Incubator Grant titled “Developing methods to promote the creation of new myelin in MS”, was awarded to Associate Professor Anthony Don.

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. 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 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 warranted 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.

In yet another example of Incubator Grants generating additional research funding, A/Prof Don was awarded a Project Grant by MS Research Australia commencing 2021 to investigate whether some MS drugs can protect and restore myelin in multiple sclerosis.

Important findings

Commencing January 2018, Professor Trevor Kilpatrick, The Florey Institute of Neuroscience and Mental Health, was awarded a 3-year Project Grant titled, “Enhancing Myelin Repair for Benefit in Multiple Sclerosis” to which the Trish MS Research Foundation contributed.

Despite some unavoidable delays resulting from the extended Melbourne lockdown period, important findings have been made.

In multiple sclerosis (MS) the protective sheath around nerves, known as myelin, is damaged and lost. This loss disrupts electrical impulses and exposes nerves to immune attack, leading to their death. Current MS therapies suppress the immune response but do not promote repair or prevent disease progression. Professor Kilpatrick and his team have shown that a protein known as Tyro3 improves myelin production and repair. The goal of this study is to establish how Tyro3 works, and the comparative benefit it is likely to provide. In an important finding, we have determined that another molecule called BDNF, which is also known to promote myelin repair, employs different signalling pathways to Tyro3, suggesting the two molecules could be used in combination for greater improvement.

We have also found that the visual system is dramatically disrupted in the absence of Tyro3. This may be because of the loss of myelin, or it may be more directly because of the loss of Tyro3 in nerves. We are now looking to answer this question, as it may be that therapies designed to activate Tyro3 may also provide direct benefit to nerves. This is important as ultimately it is damage to nerves which leads to disability in MS.

A collaborative interaction with Professor David Grayden’s group in the School of Engineering at the University of Melbourne was established and manuscripts have been published, submitted for publication and oral and poster presentations invited.

Understanding cellular mechanisms

Commencing 2019, A/Prof Simon Murray and Dr Jessica Fletcher, University of Melbourne, were awarded a 2-year Project Grant, fully funded by the Trish MS Research Foundation. The research is investigating promotion of myelin repair in the brain.

Progress in the last calendar year has been limited due to the government enforced COVID-19 lockdown in Victoria. This effectively restricted access to University buildings and services. However, A/Prof Murray and Dr Fletcher were able to gain enough access in order to complete all their animal experiments during the year and begin some analysis of the tissue. These analyses have so far shown that the novel model of demyelination they are using will enable new insights as they observe poor levels of cell survival and myelin repair. This analysis is ongoing, as is the analysis of the effect of their therapeutic candidate.

The histological analyses to examine the efficacy of the remyelinating compound are ongoing. However, earlier studies revealed that a key outcome of the work has been the establishment of a new animal model of MS where the survival and differentiation of oligodendrocytes is impaired, reflective of the current hypothesis of why remyelination fails in MS. A/Prof Murray and Dr Fletcher are making exciting progress on understanding the cellular mechanisms, with clear evidence that repeated short-term demyelination events in this model specifically impacts survival.

Success is being measured by the completion of the studies and the interest received when presented at local and international conferences (being held virtually due to the pandemic), as well as the researchers’ ability to collaborate with additional research groups in validating the next generation of the peptide mimetic that they are using to stimulate remyelination in the current study, and by the interest in this model received from potential industry partners. These are subject to ongoing interactions. The data generated is also being utilised as foundational background work for new NHMRC Ideas grant applications.

There is no change to the research plan detailed in the original application and a no-cost extension from the Trish Foundation was requested and approved in October 2020, the new completion date being October 2021. The histological studies are in progress and A/Prof Murray and Dr Fletcher are optimistic that they will be completed by October 2021.

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 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.

The COVID-19 pandemic limited their capacity to perform on-site, laboratory-based activity early in 2020. A second wave of the pandemic in Victoria further limited their ability to perform on-site activity. Procedures and protocols implemented by the University of Melbourne enabled them to maintain some essential on-site activity.

A/Prof Crouch and his team have therefore been able to maintain their work towards completing this project, albeit below normal activity levels. They anticipate producing outcomes consistent with the original nature of this project, but are behind schedule. They expect to complete laboratory-based aspects of their project within the original 3-year timeframe, but have requested an additional six months to appropriately compile and analyse all data generated.

We will look forward to receiving their final report on this exciting research.

Postgraduate Research Scholarship

Commencing January 2020, Dr Vivien Li, The Florey Institute of Neuroscience and Mental Health Victoria, was awarded a Postgraduate Research Scholarship over three years funded by the NHMRC with ‘top up’ funding by the Trish MS Research Foundation. The aim of the Project, titled “Towards developing dendritic cell therapy for multiple sclerosis based on promoting Mertk signalling”, is to study ways to dampen down the abnormal immune activation, which will hopefully lead to new ways of combatting MS.

MS is a condition resulting from damage to myelin, the insulating covering around nerve cells. It occurs when the immune system, which normally fights infections, starts to attack myelin. The immune system can be activated after exposure to certain biochemical signals. Current treatments mainly target cells in the activated immune system that directly attack nerve cells, but can suppress the immune response generally. A more potent approach may be to prevent and dampen down stimulation of the immune system. This could be achieved by giving the immune system an inhibitory rather than activating signal.

Despite not being able to begin laboratory work until 1 July 2020 and for a further 3.5 months, laboratory access being reduced to 30% of normal hours to date, Dr Li has made good progress, including collection of blood samples from patients with MS; exploring the effects of tolerogenic factors dexamethasone and vitamin D3 on expression of Mertk and other cell surface markers on dendritic cells; testing different protocols, including serum-free conditions for differentiation of monocytes into dendritic cells with good viability have the morphology of and that express known markers of dendritic cells; and verifying a protocol for efficient isolation of peripheral blood mononuclear cells from whole blood.

We look forward to learning of additional progress as Dr Li’s impressive work continues.

PrevANZ Vitamin D Prevention Trial Update – September 2020

The Trish MS Research Foundation was proud to join forces with the MS Society Western Australia, to provide vital funding to kick-start a study into Vitamin D for the prevention of MS.

The much-awaited PrevANZ vitamin D ‘gold-standard’ clinical trial, coordinated by MS Research Australia has been conducted by a team of experienced MS clinical triallists throughout Australia and New Zealand.

There is much circumstantial evidence to suggest that the lack of vitamin D is an important risk factor in the development of MS. However, there had been no robust clinical trials looking at whether taking vitamin D supplements influences the onset of MS. To address this important question, MS Research Australia set up the PrevANZ clinical trial in 2013, which was the world-first clinical trial to directly test whether vitamin D supplementation can prevent or delay MS in those at risk of developing the disease.

In this trial, people with a first episode of neurological symptoms that may be a precursor to MS (known as clinically isolated syndrome or CIS) were randomly divided into different treatment groups.

Some were given a mock medication and others were given one of three different doses of vitamin D. The trial then tested whether vitamin D supplements can delay or prevent a second episode, or attack, which would lead to a diagnosis of MS.

The trial has been running since 2013, and the last participant was recruited at the end of 2019 which brought the total number of enrolled people to 202. Each individual on the trial is given their treatment and followed for 12 months or until they display signs of a second MS attack. The last 10 participants who were enrolled in 2019 are finishing their treatment and observation period, with the last person expected to complete the trial at the end of December 2020.

Once the last person finishes the trial the statistical analysis will begin. Due to the nature of the trial the scientists aren’t allowed to know which participant is getting which treatment until the end of the trial. This is considered to be the best way to carry out a clinical trial as it prevents any bias, but unfortunately it means that we can’t have a sneak peek at the results until the end. It has been a long trial but we are awaiting the final results with great anticipation, as this is such an important question in the MS community.

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.