Despite the disruptions and challenges of the past two years, Dr Steven Petratos continues to make exceptional progress with his Trish Translational Research Project which commenced January 2020.

Animal models of multiple sclerosis (MS) are vitally important for the understanding of how brain cells die during disease progression and how specific molecules can be targeted safely to stop this. The main goal of the 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 progressive MS.

Dr Petratos and his group has uncovered that in the brains of individuals living with progressive MS, there are protein changes that cause the death of brain cells. These proteins are located in the cells that produce myelin. Importantly, the group has uncovered that a new class of medicines, known as small molecules, can access the brain to stop the death of these brain cells by protecting these proteins. This outcome has major implications in the protection of the myelin forming cells in the brain and can limit further damage imposed by the immune attack as seen in the progression of MS. Dr Petratos is now investigating whether the drug can also reverse the damage to the brain by activating stem cells to become myelin-forming cells. These outcomes will allow entry into a future Phase 2 clinical trial in Australia to stop and reverse the damage to the brain that occurs in progressive MS.

A major manuscript is currently being finalised for submission to a high-impact journal this year, as a result of progress in the first aim of the Project.

There were considerable disruptions throughout 2020 and 2021 that significantly impaired the progress of Dr Petratos’ research. Aim two is to trial the MCT8-independent thyroid hormone analogue, DITPA, as a potential therapeutic agent in demyelination to promote repair. These experiments have been planned for 2022 and will finally involve collaborators at the University Tasmania.

A new commercial agreement has commenced this month to bring the current small molecule to clinical trial in the near future and will allow Dr Petratos to recruit two full time Postdoctoral Fellows to ensure successful translation of the current research.

The Foundation is proud and honoured to be contributing to the ground-breaking work of Dr Petratos, having first funded his research in our inaugural round of funding in 2002.

The Trish MS Research Foundation contributed $200,000 to the PrevANZ Platform Program to assist the commencement of this very important trial.

The vitamin D MS Prevention Trial – PrevANZ is a world-first clinical trial that is testing whether vitamin D supplementation can prevent MS in those at risk of developing the disease.

It is a Phase IIb randomised, double blind, placebo-controlled trial testing a range of doses of oral vitamin D supplements in people with a first episode of symptoms that may be a precursor to MS (known as clinically isolated syndrome or CIS). This might include symptoms such as blurred vision (optic neuritis) or limb weakness (transverse myelitis) (these symptoms may also be described as a first demyelinating event).

The trial is testing whether vitamin D supplements can delay or prevent a second episode, or attack, which would lead to a diagnosis of MS. It is also testing the appropriate dosage levels and safety.

The need for the vitamin D MS prevention trial has arisen from a now significant body of evidence for the role that vitamin D deficiency plays in MS. However, to date there has not been a clinical trial conducted to provide the necessary evidence on the benefits that can be expected from vitamin D supplementation or the correct dose.

The expertise in Australia and New Zealand can contribute significantly to the prevention and better treatment of MS globally.  The PrevANZ analysis is ongoing and findings are expected to be available in the near future.

The Foundation has been contributing to a Project Grant titled “Enhancing Myelin repair in multiple sclerosis” at the Florey Institute of Neuroscience and Mental Health, VIC, led by Professor Trevor Kilpatrick.

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 was to establish how Tyro3 works, and the comparative benefit it is likely to provide. In an important finding, they 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.

In an unexpected but important finding, they have found that disruptions to myelin structure, such as observed in the absence of Tyro3, do not necessarily result in detectable changes in the speed of electrical impulses in nerve fibres. This finding is good news for the development of remyelinating therapies for MS, as it implies that myelin does not need to recover to pre-damage levels to have functional therapeutic benefit.

Professor Kilpatrick and his team 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. They 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.

Due to the many Melbourne lockdown periods, there have been unavoidable delays with this important work impacting Professor Kilpatrick and his team’s ability to be fully productive.  Despite the challenges, final analyses are underway with completion expected within six months.

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.

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.