Targeting Progressive MS

In January 2020 Dr Steven Petratos was awarded a 3-year Trish Translational Research Project Grant titled, “Development of a small molecule to promote neuroprotection and repair in progressive multiple sclerosis”. Dr Petratos and his team are working on developing a new drug for progressive multiple sclerosis and, despite some barriers with lockdowns in Melbourne and National border restrictions limiting Dr Petratos’ collaborative research engagement with Associate Professor Kaylene Young who is a Chief Investigator on the current grant, excellent progress has been achieved.

The first Aim of Dr Petratos and his team was to trial the MCT8-independent thyroid hormone analogue, DITPA, as a potential therapeutic agent in neuroinflammatory-mediated models of demyelination to promote neuroprotection.

Animal models of multiple sclerosis (MS) are vitally important for the understanding of how the
cells in the brain undergo change during disease progression and how we can target specific
molecules safely to stop the progression. The main goal of Dr Petratos’ research proposal is to first
understand how a specific group of molecules when decreased, limit the survival of cells (known as
‘oligodendrocytes’) that wrap a protective coating around nerve fibres (known as ‘myelin’). Such a
change can cause damage to the brain but excitingly there is a class of drugs that may be able to
stop this damage to the oligodendrocytes and myelin with the added benefit of stimulating repair
to the damaged brain, by enhancing the generation of new oligodendrocytes from their immature
cells (‘stem cells’) and making new myelin. If this project is successful, a new series of drugs will be
available for development targeting progressive MS.

The data generated demonstrates the therapeutic potential of DITPA to promote the protection of oligodendrocytes in the context of neuroinflammatory challenge and may indeed potentiate the enhancement of remyelination through the activation of oligodendroglial precursor cells (OPCs).
These experiments may well identify how OPCs can be salvaged and stimulate differentiation during MS, allowing for the repair of demyelinated lesions ultimately, potentiating neurological recovery of patients living with MS.

A new collaborative project with Medicinal Chemists at the Monash Institute Pharmaceutical Science (MIPS) has been engaged with funding through the Therapeutic Innovation Australia pipeline accelerator grant and new commercial contract that has just recently been engaged. The lead MIPS researcher on this new project is Professor Jonathan Baell.

A new commercial agreement that started in April 2021 related at bringing the current small molecule to clinical trial in the near future will allow Dr Petratos to recruit two full time Postdoctoral Fellows to ensure successful translation of the current research. Dr Petratos and his team have a Manuscript in preparation.

Dendritic cell therapy for MS

In January 2020, Professor Trevor Kilpatrick, Florey Institute of Neuroscience and Mental Health, was awarded a 3-year Trish Translational Research Project Grant titled, “Dendritic cell therapy for multiple sclerosis”.

Most current treatments for MS broadly suppress the immune system, but this can increase risks of infections and cancers. A more targeted approach is to dampen down immune cells specifically involved in attacking the nervous system. This could be achieved by giving the immune system an inhibitory signal in a targeted way. We have adopted both preclinical and clinical approaches to study this.

In the preclinical work, we aimed to determine if the ablation of an immune modulating molecule known as MERTK changes the activation profile of the immune cells responsible for producing tissue damage in autoimmune conditions like MS. Our work indicates this is not the case but leaves open the possibility that medication related activation of the MERTK protein could still have therapeutic potential.

In the human work, we have collected blood samples from controls and people with MS to test for the beneficial effects that activation of the MERTK gene might induce. From these samples, we have developed and verified techniques to isolate, purify and grow the immune cells responsible for stimulating the attack cells. In particular, we have assessed for expression of characteristic cell surface markers on these cells which, when activated, have important functions in suppressing the immune system. We have also been investigating the types of MS-associated proteins that are taken up by these immune cells and presented on their surface to initiate the immune responses responsible for causing damage. By identifying these proteins and combining them with the signals that otherwise suppress the immune system, we aim to turn off the abnormal immune activation specific to nerve cells in MS, whilst leaving the immune system still able to respond to other infections and insults.

Professor Kilpatrick and his team have collaborated with Monash University. Some experiments have been performed at the Immunoproteomics Laboratory, Monash University, led by Professor Anthony Purcell.

Making Vitamin D work for MS

In January 2020 Dr Grant Parnell was awarded a Project Grant over three years fully funded by the Trish MS Research Foundation, his Co-Investigator being Professor David Booth.

Dr Parnell’s Research Project, ‘Defining how vitamin D promotes tolerogenic dendritic cells to enable its use in combined therapy’, looks at making Vitamin D work for MS.

The aim of the project is to better understand the vitamin D response pathway in immune cells, especially identifying the processes important in making immune cells less active. This should lead to better ways to exploit vitamin D for therapy, including providing tools to assess the success or not of supplementation.

In the first 12 months of this project, Dr Parnell has performed experiments where he treated a particular type of immune cell, dendritic cells, with vitamin D and measured the response to this treatment using multiple next generation sequencing approaches. This enabled Dr Parnell and his team to identify which genes are being activated or suppressed in response to vitamin D. Initial results are showing that vitamin D reduces expression of genes that are known to be involved in inflammation and helps keep the dendritic cells in a suppressed state. Initial experiments have also been performed where they are treating these cells with vitamin D in conjunction with a secondary agent which has previously been shown to enhance the response to vitamin D in a non-immune cell type. Dr Parnell and his team are still in the process of fully characterising the response of dendritic cells to this secondary treatment. They are also planning additional experiments to target the vitamin D response pathway in ways that bypass the current homeostatic bottleneck observed with response to oral vitamin D supplementation.

The findings of Dr Parnell’s research will provide solid foundations and preliminary data for an NHMRC Ideas Grant and Investigator Grant planned for submission in 2022.

Active self-monitoring progress

In January 2020, A/Prof Anneke van der Walt was awarded a 3-year Trish Translational Research Project Grant titled, “Active self-monitoring to prospectively detect treatment failure and define subclinical progression trajectories in MS: The ACTIVE-MS Program”.

Knowing as early as possible if a treatment for MS is keeping the disease under full control is important but difficult to do in real practice.

New technology, especially health apps and smartphones, have made it possible for PwMS to collect
information in daily life. If we combine this information with routine neurology assessments, MRI data and even genetic information, we can, for the first time, get a complete picture of someone’s functioning.
This can help determine earlier if a medication is truly working and how a PwMS is really going. By
detecting subtle changes earlier, MS treatments can be used better and, it allows for a new way to
develop and test potential new treatments.

To accomplish the aims of this study, much of the groundwork for this study has been done in the year 2020. Key outcomes to date are the ethics and governance approvals and implementation of the study.

A/Prof Van der Walt and her team’s aim is to implement and validate novel tests that can be used to predict, early on, if patients with MS are likely to have a good or poor outcome. This information could be used in clinical practice to optimize treatment choice quickly and efficiently, to ensure people with MS maintain the best quality of life and productivity. To achieve this aim, they want to recruit 300 participants at four different hospitals over 12 months who will be complete a series of simple tests using their smartphone at home. Participants are also asked to share information about their MS that is collected during routine care clinic visits approximately 6 monthly, and to complete a quality-of-life questionnaire, depression and worry, and work productivity questionnaire at these routine care clinic visits for at least 12 months or the entire study duration if they choose. They are also asked to provide access to their routine magnetic resonance imaging (MRI) scans done in the 24 months preceding this study and for 36 months of observation during this protocol (estimated 4 routine scans).

Progress so far, is that the study has been approved at three of the four hospital sites. Furthermore, one site has started to recruit patients. Due to the covid restrictions, there are little to no in-patient clinic visits which has and will continue to significantly impact the speed of recruitment. An amendment has been put through to enable telehealth consenting and visits, and to optimise testing frequency. We expect all the sites to be approved and actively recruiting before mid-2021.

This study has contributed to successful collaborations and has attracted industry funding which will allow expansion of the study to an additional 6-7 sites nationally and increase the participants from 300 to 800.

Clearance of myelin debris

An Incubator Grant titled, “TREM2 and clearance of myelin debris in MS” was awarded to Associate Professor Michael Buckland, following very generous support of donors at our Trish MS Winter Wonderland Ball.

Multiple sclerosis (MS) is a disease in which the immune system attacks a protective sheath, called myelin, which covers nerves in the central nervous system (CNS-brain and spinal cord). Myelin damage is referred as demyelination and the consequence is the disruption of communication between the brain and the rest of the body. The CNS has the potential to generate new myelin (process named remyelination) after damage, but for unknown reasons remyelination fails or is incomplete in MS. Efficient removal of myelin debris is a necessary prerequisite to remyelination. In the CNS a specific cell type, called microglia is capable of clearing out myelin debris after damage. In MS lesions, microglial cells are activated and one of their functions is to pick up and digest myelin debris (process called phagocytosis). The mechanisms mediating microglia activation and phagocytosis are not known.

In this regard, A/Prof Buckland has been studying the role of triggering receptor expressed on myeloid cells 2 (TREM2), a molecule expressed on microglia membranes. As part of the grant funded by the Trish MS Research Foundation, A/Prof Buckland and his team have demonstrated that TREM2 is highly expressed on microglia cells which are active in ‘eating up” myelin debris. Furthermore, using an animal model of demyelination they have shown that activation of the TREM2 receptor led to more efficient clearance of myelin debris by microglia and promoted remyelination. This could be relevant as a possible strategy to facilitate the removal of damaged myelin from the tissue and thus potentially enhance remyelination in people with MS. A/Prof Buckland and his team are continuing their research into how TREM2 promotes myelin clearance with the ultimate aim of informing intelligent drug design to accelerate lesion repair in MS.

This pilot proposal will allow generation of preliminary data that will be used to apply for larger research grants to MS Research Australia and the NHMRC.

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.