Potential “best-in-class” therapeutics

Commencing January 2020, Dr Steven Petratos, Monash University, was awarded a 3-year Trish Translational Research Project Grant titled, “Developing a new drug to repair the brain in Multiple Sclerosis”.

Dr Petratos and his team have been looking to repurpose a drug previously approved for use in a different neurological condition.  He had previously shown that this drug may slow the progression of MS in a laboratory model of MS.

Despite the disruptions and challenges caused by COVID early in his work, Dr Petratos has made exceptional progress.

Dr Petratos and his group 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 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 has been investigating whether the drug can also reverse the damage to the brain by activating stem cells to become myelin-forming cells. In experiments with the animal model of MS, his team has now shown that the drug can repair the damaged myelin through a process known as remyelination. 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 service agreement has been now entered into with Monash University and the commercial company NeuOrphan Pty Ltd that will progress this drug toward the Clinical Trials.

Dr Petratos and his team have been collaborating with researchers at the University of Tasmania trialling the MCT-8-independent thyroid hormone analogue DITPA, as a potential therapeutic agent in demyelination to promote protection and repair of the brain during the immune attack against myelin. He is also the holder of a patent for the use of this drug for neurological conditions that has been granted in Australia, US, Canada and Europe.

The repurposing of the drug DITPA may have the potential to become a “first-in-class” therapeutic for individuals living with MS if clinical trials demonstrate that it can protect and potentially repair areas of the brain, spinal cord and optic nerve that have been damaged due to the disease. With further commercial funding on the horizon, this work will promote the development of potential “best-in-class” therapeutics that may promote substantial pharmaceutical industry interest in a series of new medications formulated for protection and repair of the brain during MS.

The Trish 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.

Dr Petratos, working with Professor Paul Stupple, The Monash Institute of Pharmaceutical Sciences, has been awarded a 2-year Trish Translational Research Project Grant commencing January 2023 titled, “Development of Small Molecules to Promote Remyelination in Multiple Sclerosis”.  The Foundation’s volunteer team and our generous Sponsors and donors look forward to learning of more advancement of Dr Petratos’ promising research.

Cellular therapy

Commencing January 2020, Professor Trevor Kilpatrick, University of Melbourne, was awarded a 3-year Trish Translational Project Grant titled, “Developing cellular therapy to treat multiple sclerosis”.

The funds were used in a project to develop a therapy for multiple sclerosis (MS) based on using immune cells from the blood of patients with MS. These immune cells are treated with anti-inflammatory signals in the laboratory and will then be re-administered back to the patient, where they selectively target and dampen down the disease-causing cells of the immune system that otherwise promote inflammation and lead to nerve cell damage in MS. This therapeutic approach represents a potentially more targeted and individualised way to treat MS compared to current therapies, which broadly suppress the immune system and can increase risks of infections and cancers.

The activities which have been undertaken include:

  1. Refining techniques to grow these immune cells from blood samples collected from patients and defining culture conditions that can modify the behaviour of these cells that normally process proteins associated with MS to assume protective/anti-inflammatory rather than disease-inducing/pro-inflammatory characteristics. Professor Kilpatrick and his team have studied one such anti-inflammatory factor, dexamethasone, in-depth and characterised its effects in reducing the expression of proteins on the cell surface and the release of chemical signals that normally activate the immune system to cause inflammation and disease.
  2. Identifying certain MS-associated proteins that are taken up by immune cells and presented on their surface to initiate the immune responses responsible for causing damage in MS. By identifying these proteins and combining them with signals that suppress the immune system, Professor Kilpatrick and his team aim to turn off the abnormal immune activation targeted towards nerve cells in MS, whilst leaving the immune system still able to respond to other infections and insults.
  3. Collecting blood samples from nearly 200 patients with MS and testing for the presence of a gene that is a known risk factor for MS. This gene is involved in presenting MS-associated proteins on the surface of immune cells and could influence an individual’s immune responses and capacity to respond to this type of therapy.

Professor Kilpatrick and his team have been able to grow immune cells derived from patients with MS in the laboratory and promote enduring anti-inflammatory characteristics in these cells by treating them with dexamethasone. They have also identified certain MS-associated proteins that are presented on immune cells to activate the immune system, and that their expression can be modified by dexamethasone. The next steps will involve treating the immune cells with relevant MS-triggering proteins but to do so together with dexamethasone to ‘trick’ them into inducing an anti-inflammatory rather than pro-inflammatory response.

If successful, this Project could lead to clinical trials of a new treatment approach for MS which is more selective and potent than current therapies.

Professor Kilpatrick, working with Dr Vivien Li, has been awarded another 3-year Trish Translational Research Project Grant commencing January 2023 titled, “Advancing tolerogenic dendritic cell therapy for multiple sclerosis toward clinical translation” and we will look forward to more exciting progress as Professor Kilpatrick and Dr Li’s impressive work continues.

NHMRC ‘top up’ funding

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 National Health & Medical Research Council with ‘top up’ funding provided 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” was to study ways to dampen down the abnormal immune activation, which would hopefully lead to new ways of combatting MS.

Despite being delayed by Covid, with laboratory access being reduced early in her work, Dr Li 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 and with tolerogenic potential.

Dr Li has been granted a 6-month extension by the NHMRC for COVID-19 related delays and her Postgraduate Scholarship is now being continued until September 2023.

Key Advances

In 2019 Dr Justin Garber, the University of Sydney, was awarded a Trish MS Research Foundation Postgraduate Scholarship titled “Using MRI to measure MS severity and progression”.

Due to being appointed to a Staff Specialist Neurologist position at Westmead Hospital, as Director of the MS Clinic, Dr Garber completed the final year of his Postgraduate Scholarship over two years, with completion of data analysis, conference abstracts, journal articles and the PhD thesis being written.

Dr Garber’s research has led to a number of key advances in the understanding of the disease mechanism that underlie multiple sclerosis, especially in the way MS damages the network structure of the brain and how that mediates neurological disability. A promising biomarker has been developed that can predict which patient with progressive MS will worsen in their neurological disability over 2 years and which patients will not, allowing for better prediction models, as well as the potential identification of patients in need of immediate intervention. This research will guide future treatment trials into progressive forms of MS.

Dr Garber has led a number of Research conference presentations: “Implications for the registration of white matter structures in MS connectome analysis”, “Quantifying the T1 hypo-intensity of MS lesions” and “Incorporating Cumulative Damage Along White Matter Tracts in Structural Connectomes in MS”.

This project finished with the completion of Dr Justin Garber’s PhD, which is the culmination of 4 years of detailed longitudinal study of patients with progressive MS. This research opens several further avenues of inquiry and will be built upon through further research endeavours in the future notably with Dr Garber’s Neuroimmunology clinical research practice at Westmead Hospital in Sydney, as well as through the Brain and Mind Centre MS clinical trials research unit at the University of Sydney.

Research leading to a $1.1M NHMRC Ideas Grant

Commencing January 2019, Dr Junhua Xiao, the University of Melbourne, was awarded a 3-year Project Grant titled “How neurons regulate cortical and subcortical remyelination”.  Dr Xiao subsequently left the University and her Project Grant was awarded to A/Prof Simon Murray who has continued her important work.

In this research the scientists have been looking at a protein called TrkB which is made in the nerve cells in the brain and seems to be important in the remyelination process.  Using a combination of ground-breaking scientific approaches, the project has been looking at what happens to the remyelination process in cells in the presence and absence of TrkB.

A/Prof Murray has sent the following report:

“This grant has continued to progress well.  We have used an experimental model of central nervous system demyelination to dissect the role that a molecule, called TrkB, exerts upon myelin repair.  We have been working on the TrkB molecule for some time and we believe it holds promise as a therapeutic target for repair in MS.  In these particular experiments, we interrogated the role that TrkB expressed on nerve cells exert upon myelin repair.  After extensive analysis of a number of experimental cohorts, the data are clearly demonstrating that neuronal TrkB exerts little effect upon myelin repair.  These data were not as expected and quite surprising, but is nevertheless an important finding and has helped us refine our hypotheses for future experiments and proposals.  I would like to acknowledge a PhD student in the lab, Ms Sangwon Yoo, for undertaking some of these analyses.  These experiments have formed a substantial part of her PhD thesis which we hope to submit by the end of this year.

This grant had an additional component that examined the nature of the interaction between oligodendrocytes and the nerves they myelinate.  Intriguingly, we are finding that the TrkB molecule is exerting significant differences in the way the oligodendrocytes make initial contact with axons.  This is novel and we are continuing to examine this.  This is all the more intriguing, as despite these differences in the initial contact, myelin repair appears to proceed unimpeded.

Finally, I would just like to add that grants such as these are extremely important to the lab, they really help us keep together in a very tight funding environment.  On the up-side, I am very pleased to let you know that the lab received a 5 year, $1.1M NHMRC Ideas Grant to continue our MS research.  This was announced at the end of 2021 and came into effect this year.  This new Ideas Grant is related to the work undertaken in the Trish grant, still focussing our attention on TrkB in remyelination.  So we are grateful for the time and effort you, your Foundation and your donor groups put in, they really help the lab along.”

Due to the pandemic, a revised completion date to 31st December 2022 for A/Prof Murray’s Project Grant was requested and approved.

Active Participatory Health Monitoring

Commencing January 2020, A/Prof Anneke van der Walt was awarded a three-year Trish Translational Research Project Grant titled, “Active Participatory Health Monitoring in people with Multiple Sclerosis (Active-MS)”.

The aim of the Project 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 aim to recruit 300 participants at four different hospitals over 12 months who will 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 chose. 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 all four hospital sites, all of which have Ethics and Governance approval. The first patient was recruited in November 2020, and there was a total of 140 patients enrolled in the study on 31st December 2022.

With this Project commencing January 2020, Covid 19 had a large impact on recruitment and resources as staff were redeployed to other areas to assist in the management of Covid.  Due to these constraints, approval has been granted to extend this study, the new completion date being 31 December 2023.

Unfortunately, due to significant under recruitment, one of the sites has been closed for further recruitment. However, Alfred Health will continue recruitment past their original target to increase the total recruitment number as much as possible.

This study has contributed to A/Prof van der Walt and her team’s successful collaboration with Redenlab, SNAC and Roche.

One of the three apps used for testing in this study, Floodlight Open, closed in April 2023. Therefore, the team has started collaborating with Roche to move to their new app Floodlight MS. The tests within the new app are identical; however, this app is not open access and requires collaboration with Roche. To make it a smooth transition between the two apps, we have made the necessary amendment to the protocol and PICF. These have been approved by Alfred ethics. The other three sites have also submitted the amendment.

A/Prof van der Walt and her team aim to finish recruitment mid 2023 at all sites. In addition, they will continue their monitoring of the adherence and data quality to ensure that study objectives can be met and are aiming to produce publications after year 3.  We look forward to analyses and publication of the findings of this study.

The vitamin D response pathway

The Trish Foundation is currently funding Dr Grant Parnell’s research titled, “Defining how vitamin D promotes tolerogenic dendritic cells to enable its use in combined therapy”.  The research is being carried out at The Westmead Institute for Medical Research / The University of Sydney.

The aim of this 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.

To date in this project, we have performed experiments where we 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 us to identify which genes are being activated or suppressed in response to vitamin D. Our 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. We have also performed initial experiments where we 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. We are still in the process of fully characterising the response of dendritic cells to this secondary treatment. We 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.

2021 saw significant disruption to the progress of this work. Many of our experiments require 2-week cell cultures and subsequent down stream processing. For a large proportion of the year we were either on alert for a potential shutdown of WIMR (where the lab is based) or prevented from attending WIMR. We are therefore intending to request a 12 month extension of the duration of this Grant to enable us to make up for the time lost due to the COVID-19 disruptions. Whilst some level of disruption persists (eg isolations if testing positive or symptomatic), we have now returned to the lab without restrictions and are making good progress with the project.

A revised completion date for Dr Parnell’s Project to 30 December 2023 has been approved.

In August 2021 Dr Parnell was successful in obtaining a full time continuing position as a lecturer at the University of Sydney, with 40% of his time dedicated to research.  This will enable Dr Parnell to continue in MS research for many years to come, as well as contribute to the education of the next generation of medical researchers.  Dr Parnell has a great team working with him to keep the research progressing and is looking to recruit some additional research staff now that work is returning to the new normal.

We look forward to Dr Parnell and his team making additional progress with this important research.

Excellent progress

Commencing January 2022, Dr Izanne Roos, University of Melbourne was granted a 3-year Trish Translational Research Project Grant titled, “Personalised therapy to prevent disability in aggressive multiple sclerosis”.

Dr Roos’ diligent, very hard work is enabling excellent progress to be achieved.

In this research project, Dr Roos and her team are aiming to validate statistical models which can predict an individual’s risk of developing aggressive MS at the earliest stages of MS. They will then establish whether early use of the most potent therapies can prevent aggressive disease in those patients at high risk. They aim to achieve this by using data from big MS registries (MSBase, an international registry, and OFSEP, the French National registry), and a cohort of patients with MS who are followed from early after MS onset from Barcelona, Spain. The focus in 2022 was on setting up the necessary collaborations, and obtaining data from all sources, while abiding to the requirements of the European General Data Protection Regulation. All data had been obtained by December 2022, and data mapping and quality control procedures have been applied.

Several key outcomes had been achieved in the first year of the Project:

  • Establishment of collaborations with two large MS teams led by eminent leaders in the field of MS and neuroimmunology.
  • Full execution of two GDRP compliant agreements and subsequent data transfer.
  • Completed data mapping for both Projects 1 and 2.
  • Preliminary results from models 1 and 2 of project 1, with resultant further refinement of the included cohorts as agreed by all parties.
  • Advancement of the statistical and methodological expertise required for project completion as evidenced by first author publication in Multiple Sclerosis Journal by CIA Roos (Roos et al. Comparative effectiveness in multiple sclerosis: A methodological comparison.)

These outcomes are key to the subsequent analytical steps and have occurred in line with the proposed timelines.

In 2023 Dr Roos and her team are focusing on the completion of project 1, and completion of the first two analyses of project 2.  Project 1 involves the validation of prognostic models for the development of aggressive MS.  The results of the validation models will be submitted for publication in a peer-reviewed international journal.

Project 2 will focus on optimal treatment approaches for patients at highest risk of aggressive MS.  Dr Roos aims to explore this in a series of analyses. Analysis 1 will compare the odds of aggressive MS among high-risk patients treated with high-efficacy vs standard/no treatment, using marginal structural models. It will also compare the risks of relapses and disability worsening. Analysis 2 will use similar methodology to study the interaction of therapy with time from MS onset to start of high-efficacy therapy, with the aim of evaluating the influence of the timing of treatment start. Dr Roos aims to have completed both these analyses by the end of 2023, with planned manuscript submission in early 2024.

If Dr Roos is successful in validating statistical models which can predict an individual’s risk of developing aggressive MS at the earliest stages and then establishing whether early use of the most potent therapies can prevent aggressive disease in those patients at high risk, people living with – or diagnosed with – aggressive MS would benefit enormously.  Dr Roos is making great inroads into achieving this.

PrevANZ Findings

On 6th June 2011 the Foundation was pleased to announce we had joined forces with the MS Society Western Australia to provide vital funding to initiate a world-first clinical trial of Vitamin D for the prevention of MS. This Project could not have proceeded without the contributions of the Trish Foundation and the MS Society of WA and was to be the first in the world with the power to prove that Vitamin D is a safe and effective method for preventing MS.

At the time, the Executive Director of MS Research Australia, Jeremy Wright (who is now a Board member of the Trish Foundation) said, “The Trish Foundation was the first to recognize how important it is to test this Vitamin D intervention and to see if it can save the onset of MS. Their support is inspired and to be applauded.”

There had long been interest in the possible benefits of vitamin D supplements for those living with MS and whether they can be used to prevent the development of MS. That is because the risk of developing MS can vary depending on latitude, with those living furthest from the equator more likely to be affected by the disease. In Australia, those living in the north of the country are less likely to develop MS than those in the south.

It has long been hypothesised that this is brought on by a lack of sunlight, which could potentially lower vitamin D levels. To test this hypothesis, MS Research Australia, with support from the Trish Foundation and MS Western Australia, established the world’s first clinical trial involving 204 people from Australia and New Zealand.  A small, highly dedicated team worked for many years on this study, to establish the potential benefit of oral vitamin D supplementation to prevent new MS disease activity in people who had just had their first attack of MS. Each person taking part in the trial was then randomised to one of three different daily doses of vitamin D (1000 IU (international units), 5000 IU or 10000 IU), or a placebo (no vitamin D). Vitamin D was used as a standalone therapy – the participants were not on other disease-modifying drugs for their MS.

“Vitamin D supplements do not prevent the development of Multiple Sclerosis.” That is the finding from PrevANZ, the ground-breaking clinical trial to determine if oral vitamin D supplements can delay the onset of MS.

Professor Helmut Butzkueven, Chair of the PrevANZ Steering Committee said the participants were then followed for 48 weeks to determine whether they went on to develop MS.

“We showed conclusively that doses of up to 10,000 international units per day did not reduce MS activity compared to those who did not take vitamin D,” Professor Butzkueven said.

Professor Bruce Taylor, also from the PrevANZ Steering Committee, understands this might be seen as a disappointing result, but says it is a very important one.

“We are now eagerly awaiting the results of D-LAY MS, a French study with very similar design.

“On behalf of the entire study team, we wish to thank all the study participants and investigators for their participation and dedication over so many years”, Professor Taylor said.

Further research is underway to understand more about the effects of vitamin D on the immune system and nervous system in this group. More work is needed to uncover the mechanisms underpinning the role of latitude and sunshine in the risk of developing MS.

Industry funding attracted

Commencing January 2020, A/Prof Anneke van der Walt was awarded a three-year Trish Translational Research Project Grant titled, “Active Participatory Health Monitoring in people with Multiple Sclerosis (Active-MS)”.

The aim of the Project 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.

A/Prof van der Walt and her team’s progress so far, is that the study has been approved at all four hospital sites, all sites having Ethics and Governance approval. All sites have commenced recruitment. The necessary technology to enable and ensure the collection of high-quality data have been developed. Due to the Covid restrictions, there have been little to no in-patient clinic visits which has and will continue to significantly impact the speed of recruitment. To reduce this impact, an ethics amendment enables telehealth consenting and visits.

Covid 19 has also had a large impact on recruitment and resources as staff have been redeployed to other areas to assist in the management of Covid. Easing of Covid restrictions will increase the number of in-clinic visits and boost the recruitment rate. Due to these constraints, approval has been granted to extend this study, the new completion date being 31 December 2023.

A/Prof van der Walt and her team have attracted industry funding from Roche pharma.  This will allow them to expand the study to an additional 6-7 sites nationally and increase the participants from 300 to 600. This study has also contributed to successful collaborations.