Progressive MS Alliance Grant Funding
Newswise — The International Progressive MS Alliance has awarded its first round of 22 research grants to investigators in 9 countries, with the goal of removing barriers to developing treatments for progressive MS. The Alliance is a worldwide collaborative focused on finding solutions to progressive forms of multiple sclerosis that have so far eluded the scientific community.
This first round of funding launches an ambitious program that will cumulatively invest €22 million over the next five years and will forge international collaborative research networks -- leveraging research already underway and stimulating new research through the Alliance’s significant funding programs.
Following is a summary of each project. To learn more visit www.ProgressiveMSAlliance.org or http://newswise.com/images/ee/article_supp/Alliance.pdf
AUSTRALIATitle: Limiting axonal degeneration in a model of multiple sclerosisPrincipal Investigator: Steven Petratos, Ph.D.Institution: Monash UniversityAmount Awarded: €74,326Summary: Nerve fiber damage is thought to underlie progressive disability in MS. This team has been working to understand the biological processes that lead to nerve degeneration. They have found evidence that one protein, Nogo-A, may play a role in this damage, and they have also found a possible strategy for protecting against it. They are now proposing to investigate this further by deleting this protein from nerve cells in mouse models, and then observing the effects starting at the onset of MS-like disease. Then will then attempt to block Nogo-A using novel strategies for delivering agents to the brain and spinal cord.What does this mean for people living with progressive MS? This study may yield a new strategy for developing a therapy that limits damage to nerve cells and stops the progression of MS.
BELGIUMTitle: Towards a shared data repository to enhance the standards of rehabilitation in MS: Feasibility, capacity building and proof-of-concept on exercise therapy & mobility measuresPrincipal Investigator: Peter Feys, Ph.D.Institution: Hasselt UniversityAmount Awarded: €74,985Summary: Exercise therapy is a potentially effective treatment for people with MS. However, despite an explosion of research on physical rehabilitation and exercise, it is not yet clear whether beneficial effects are equally present in progressive compared to relapsing-remitting type of MS. One issue has been the small size of studies. This project proposes to prepare the construction of a large, shared data repository that would be established by retrieving data from published studies and new data entered by clinical and research centers. This would enable researchers to investigate questions on the effects of specific exercise interventions and settings, or on the appropriateness of different outcome measures. Ultimately, this will lead to improved standards in MS rehabilitation practice.What does this mean for people living with progressive MS? This endeavor could enhance the ability to determine the best rehabilitation and exercise interventions for people with progressive MS, and provide the data needed to advocate for its widespread use to improve lives.
CANADATitle: T-cell activation molecules and progressive MSPrincipal Investigator: David Haegert, M.D.Institution: McGill UniversityAmount Awarded: €74,739Summary: Early in the course of MS it is difficult to know whose disease will progress and whose will not. This team proposes to identify and test potential biomarkers – molecular signatures – in the blood to determine if they can be used to predict whether someone with MS will show rapid or slow disease progression. They will test blood samples from people with MS who participated in clinical trials in the past, and whose course of disease progression is known. If the biomarker is indeed increased in people with rapidly progressing MS and not in those whose MS is more benign, this biomarker could be developed as a test to predict disease progression and identify people who need more aggressive treatment.What does this mean for people living with progressive MS? Finding a biomarker that can be tested in blood samples of people with MS could help predict the rate of disease progression and help determine the most appropriate therapy.
ITALYTitle: Can the degree of meningeal inflammation and cortical pathology be used to stratify early progressive MS patients?Principal Investigator: Massimiliano Calabrese, M.D., Ph.D.Institution: University of VeronaAmount Awarded: €68,673Summary: This team has previously shown that the amount of damage to the grey matter on the surface of the brain in early stages of MS associates with an increased chance that the future disease course will be more severe. Now they are analyzing the cerebrospinal fluid that surrounds the brain and using MRI brain scanning to examine brain tissue from people with progressive MS obtained via autopsy. They are examining types and quantities of messenger proteins and molecules that may be associated with damage seen by MRI scanning. This combined approach may identify both the molecules and brain imaging signals that predict a more severe disease, so that neurologists can recognize and address a more severe course of MS before quality of life is severely affected.What does this mean for people living with progressive MS? Being able to address and vigorously treat a severe course of MS as early as possible is crucial to stopping progression in its tracks.
NETHERLANDSTitle: Immune-primed microglia: a factor underlying progressive multiple sclerosisPrincipal Investigator: Sandra Amor, Ph.D.Institution: University Hospital Vrije Universisteit-VUMCAmount Awarded: €74,999Summary: This team aims to investigate the specific role of brain cells called “microglia” on MS progression. Both primary and secondary progressive MS start around 35 years, irrespective of relapses, suggesting that age may be a factor. Microglia help to activate the immune system (which attacks the brain and spinal cord in MS), but also dampen inflammation, producing substances that promote repair. A subtle balance exists between these two opposing functions. With increasing age, this balance shifts, and microglia become less effective in their protective functions, and more active stimulating damage, possibly explaining why progression increases with age. This team proposes to examine microglia from people with different types of MS, and people without neurological disease, taking into account their ages. This may reveal differences between "young" and "old" microglia, and differences between people with and without MS. They are extending these experiments in mice with relapsing-remitting MS-like disease that later becomes progressive. What does this mean for people living with progressive MS? Understanding the impact of age on inflammation and repair may help to identify new avenues to counteract age-induced changes and prevent them from causing MS to progress.
Title: Discovery of biomarkers reflecting progression pathophysiology for primary progressive MS subtype by applying next generation sequencing and novel multiplex aptamer approach.Principal Investigator: Charlotte Teunissen, Ph.D.Institution: University Hospital Vrije Universisteit-VUMCAmount Awarded: €74,250Summary: MS, whether relapsing-remitting or primary progressive, progresses differently in different people, suggesting that disease progression occurs for different reasons in different people. Early in the disease it is difficult to predict the course that any individual will experience, which makes it difficult to determine optimal treatment approaches. This group proposes to investigate blood samples from people with different subtypes of MS to identify disease activity and potential biomarkers – or molecular signatures -- that will differentiate relapsing-remitting from primary-progressive MS. They also aim to find ways to discriminate between people who have slow versus rapid progression. Identifying biomarkers that identify the underlying disease activity responsible for a person’s disease course will allow prediction of the response to therapy and new targets for novel therapies.What does this mean for people living with progressive MS? Having reliable biomarkers would greatly increase the ability to determine the best therapy for an individual, and offer clues to the underlying causes of MS progression.
Title: Inflammation drives mitochondrial dysfunction and associated neurodegeneration in MSPrincipal Investigator: Jack van Horssen, Ph.D.Institution: University Hospital Vrije Universisteit-VUMC Amount Awarded: €75,000Summary: One of the main reasons that there are no specific therapies for progressive MS is that we know little about the processes underlying worsening disability. It has become increasingly clear that injury and loss of nervous tissue, also known as neurodegeneration, largely drives progressive MS. This team and others have shown that mitochondria, the tiny energy factors within cells, are dysfunctional in nerve cells of people with progressive MS and this may contribute to neurodegeneration. Nerve cells rely heavily on an adequate supply of energy to facilitate conduction of signals and therefore proper mitochondrial function is crucial. Eventually, impaired mitochondrial function will lead to severe nerve cell injury and loss. Now this team is unraveling which immune cells and associated inflammatory products may be responsible for mitochondrial dysfunction in nerve cells of mice and in cells isolated from people with MS. What does this mean for people living with progressive MS? This project will significantly contribute to our understanding of mechanisms underlying progressive MS, and provide a potential basis for the development of new therapeutics to stop neurodegeneration and progression.
SPAINTitle: Search of biomarkers in patients with progressive multiple sclerosisPrincipal Investigator: Xavier Montalban, M.D, Ph.D.Institution: Institut de Recerca Vall d’Hebron (VHIR) Amount Awarded: €74,250Summary: Ending progressive MS is an urgent and unmet need that must be overcome so that people can live their lives without the uncertainty of what tomorrow will bring. Long-term follow-up of people with progressive MS is crucial to reducing this uncertainty and establishing a disease prognosis based on how the disease course evolves. This research team has followed a group of individuals with progressive MS for more than 10 years, and has carefully collected all the necessary clinical, radiological, and biological information to propose “biomarkers” that might be used as flags to predict individuals’ prognosis of progressive MS. Now they are using innovative technologies to mine this information for the identification of these predictive biomarkers.What does this mean for people living with progressive MS? It is crucial to have ways to predict an individual’s course of MS early on to help make rational treatment decisions. This project may not only reveal useful biomarkers, but also help to identify the molecular mechanisms that operate during progressive phases of MS and which might be blocked by therapies to stop progression.
SWEDENTitle: MS genetic and environmental factors for severity/progression through studies of complications including spasticity, pain, depression,urogenital complications, sick leave/pension/income using Swedish registries for comparisons/interaction analysis.Principal Investigator: Tomas Olsson, M.D., F.R.C.P.(C), Ph.D.Institution: Karolinska InstituteAmount Awarded: €74,250Summary: MS is unpredictable; this team is looking for a way to change that. They are studying risk genes, and lifestyle/environmental factors (such as smoking and previous infections), and their potential interactions, in a large Swedish, nationwide database. They have collected blood samples for 10 years from 8000 persons with MS and 6500 matched controls without MS, collecting data on disease development. Genetic information and the most critical lifestyle/environmental factors will be assessed for their association with MS complications such as spasticity, as well as MS severity and time to progression. The team hopes to identify genes and lifestyle factors related to outcomes and quality of life. What does this mean for people living with progressive MS? This study could pave the way for new therapeutic strategies, and help define lifestyle and environmental factors that may provide clues to preventing or stopping MS.
Title: Intrathecal monoclonal antibody therapy and cerebral microdialysis in progressive multiple sclerosisPrincipal Investigator: Anders Svenningsson, M.D., Ph.D.Institution: Umeå UniversityAmount Awarded: €74,800Summary: Small clusters of immune cells called B cells are commonly found within the brains of people with progressive MS, which points to the presence of hidden and potentially damaging immune activity. Rituximab is an agent that eliminates B cells. Trials using rituximab in progressive MS so far have not been successful, possibly because rituximab is unable to access these particular B cell clusters. This team is administering rituximab directly into the spinal fluid (intrathecally). In an ongoing trial they have been treating people with progressive MS with this method, with some success. Now, while continuing to test this treatment, the team will sample immune messenger chemicals inside the brain using a device called a microdialysis catheter. They plan to insert this device in 20 people to better determine outcomes of the treatment and, for the first time, attempt to monitor immune activity inside the brains of people with progressive MS. What does this mean for people living with progressive MS? This study can answer the question of whether there is ongoing inflammation in the brains of people with progressive MS, and whether rituximab has potential as a treatment for progression.
UNITED KINGDOMTitle: The effects of oculomotor retraining on upper and lower limb function in progressive MS. A proof of concept studyPrincipal Investigator: Jonathan Marsden, M.Sc., Ph.D.Institution: Plymouth UniversityAmount Awarded: €74,895Summary: Balance problems typically result in a swaying and “drunken” type of gait known as ataxia. People with MS who have ataxia find it difficult to perform tasks such as manipulating tools, balancing, and avoiding obstacles. One reason for this is that they often move their eyes involuntarily from side-to-side and have inaccurate eye movement. In people who don’t have MS but have ataxia for other reasons, this team has shown that inaccurate eye movements directly lead to uncoordinated arm and leg movements, and, importantly, that eye movements can be retrained, leading to improved walking and balancing. Now they are proposing to measure eye movements in 30 people with progressive MS who have symptoms of ataxia, and to also explore whether a 4-week program of eye movement retraining can improve their mobility. What does this mean for people living with progressive MS? This study could lead to the further testing of a strategy to reduce ataxia in people with MS, potentially providing a solution that improves their daily lives.
Title: Novel enabling infrastructure for outcomes monitoring: dynamic remote performance capture to assess disability in progressive multiple sclerosisPrincipal Investigator: Paul Matthews, M.D., Ph.D.Institution: Imperial College LondonAmount Awarded: €74,995Summary: Development of new medicines for progressive MS is difficult in part because measures of disability that are insensitive to the smaller changes that may be meaningful to a person with MS. People with MS also appreciate changes in their symptoms on a day-to-day basis that are not well captured in periodic, single tests done as part of clinic visits. The popularity of small movement sensing devices called “actigraphs” that allow activity to be continuously tracked, stored and then downloaded onto a computer provides an illustration of one of the kinds of technology that might help. This team proposes to conduct a pilot study to determine if actigraphs can provide a useful tool to measure and track disability in people with progressive MS. If these devices could be adapted for use for people with MS, doctors and researchers would be able to understand how people are performing in their homes, offices and communities and get a real-time sense of outcomes from treatments.What does this mean for people living with progressive MS? Providing real time information about symptoms and disability progression can help to track the course of MS and determine effectiveness of treatments designed to stop progression.
Title: Cause and consequences of mitochondrial injury in progressive multiple sclerosisPrincipal Investigator: Don Mahad, M.D., Ph.D.Institution: University of EdinburghAmount Awarded: €74,868Summary: In MS, myelin, the fatty substance that surrounds and protects nerve fibers, is destroyed. This loss of myelin can affect the function and survival of nerve cells. Some research suggests that nerve cells may die due to damage to tiny energy-producing factories inside the cells, called mitochondria. The DNA that is found in degenerating mitochondria in nerve cells in MS often contains mutations. This team proposes to develop a test to determine the susceptibility to mitochondrial DNA mutations in MS, and will investigate the features of the abnormal mitochondria that result from the loss of myelin. The results from this study may identify ways to protect the nerve fibers and their mitochondria in people with progressive MS.What does this mean for people living with progressive MS? If this research verifies a crucial role for damaged mitochondria in MS progression, it may identify new approaches to protecting nerve cells from harm to stop or prevent progression.
Title: Establishing the resource for a genetic analysis of progressionPrincipal Investigator: Stephen Sawcer, Ch.B., F.R.C.P., M.B., Ph.D.Institution: University of CambridgeAmount Awarded: €72,778Summary: By bringing together dedicated researchers from 15 different countries, the International Multiple Sclerosis Genetics Consortium (IMSGC) has already successfully used genome-wide association studies to identify over 100 genetic variations influencing the risk of developing MS. The team now proposes to leverage the compiled DNA samples from 50,000 people with MS to compare gene profiles among 1000 people with the most severe course against 1000 people having the most benign course. The collecting together and collating of these samples should provide the first resource with sufficient power to identify gene variants that influence progression in MS.What does this mean for people living with progressive MS? This resource could provide a means to identify the key biological processes determining progression in MS, and point the way to selecting rational targets for therapy development.
UNITED STATESTitle: New mouse model of repeated demyelination that results in a progressive neurological declinePrincipal Investigator: Robin Avila, Ph.D.Institution: Renovo Neural, Inc.Amount Awarded: €75,000Summary: Multiple sclerosis involves repeated immune system attacks on the brain and spinal cord. Most people begin with a relapsing-remitting disease course of MS, which eventually develops into a progressive neurological disease course called secondary-progressive MS. Most treatments are approved for the people who are still experiencing relapses. One of the obstacles to developing treatments is the lack of animal models that mimic non-relapsing secondary-progressive MS. The purpose of this proposal is to develop a mouse model that will serve as a platform for testing new experimental strategies for stopping MS progression. The investigators propose to replicate some of the repeated injury that occurs over time and determine and document the longer-term consequences of that injury.What does this mean for people living with progressive MS? Developing a model for testing whether therapies can stop MS progression is a critical step in bringing these strategies from the laboratory to the clinic where they can end progression in people with MS.
Title: Genetic analysis of high-resolution imaging endophenotypes in MS progressionPrincipal Investigator: Sergio Baranzini, Ph.D.Institution: University of California, San FranciscoAmount Awarded: €75,000Summary: Screenings of the entire complement of common genes, (genome) have identified more than 100 genes associated with a person’s susceptibility to MS. Yet a significant proportion of the genetic risk to MS remains to be explained, and to date gene links to disease course have been weak. This team has evidence suggesting that the varied courses of MS seen across people is in part instructed by genes, and the team is studying specific gene regions that associate with certain hallmarks of progression, such as the total area of nervous tissue damage, brain volume loss, and decline in the visual system. In this study, the team proposes to integrate gene profiling, brain MRI, optical coherence tomography (which captures images of nerve structures behind the eye), together with sophisticated bioinformatics, to uncover genetic “signatures” that are associated with different types of disease course among hundreds of people.What does this mean for people living with progressive MS? If this project successfully enables better understanding of how and why MS progresses in certain people, it would enable doctors to give more accurate prognoses to individuals, inform treatment decisions, and help stop progression in its tracks.
Title: A phase 1 open-label trial of intrathecal rituximab for progressive multiple sclerosis patients with magnetic resonance imaging evidence of leptomeningeal enhancementPrincipal Investigator: Peter Calabresi, M.D.Institution: Johns Hopkins UniversityAmount Awarded: €74,998Summary: Multiple sclerosis involves an immune system attack on the brain and spinal cord. Within the tissues covering the brain and spinal cord (meninges), abnormal clusters of immune B cells have been described in progressive, and to a lesser extent, relapsing MS. These clusters are associated with increased damage to the adjoining surface of the brain and may play a role in MS progression. Rituximab is an agent that can eliminate B cells. This team proposes to use a special MRI technique to identify these cell clusters in 12 people with secondary- or primary-progressive MS. In people who have them, the team will then conduct a pilot test of rituximab delivered directly into the spinal fluid (intrathecally), and will evaluate the safety and potential effectiveness of this method for reducing the immune cell clusters. What does this mean for people living with progressive MS? This study may point to a new treatment approach for stopping MS progression in some people with MS, and also provide a new biomarker for tracking the success of this treatment.
Title: Treating new learning and memory deficits in Progressive MS: the modified Story Memory TechniquePrincipal Investigator: Nancy Chiaravalloti, Ph.D.Institution: Kessler Foundation Research CenterAmount Awarded: €74,976Summary: Cognitive function, especially learning and memory, impacts a substantial proportion of people with MS. This team has demonstrated that the modified “Story Memory Technique” (mSMT) – which helps people to learn new information and remember older information using imagery and context – improves learning, as well as laboratory measures of memory and activities of everyday life. However, this treatment has not yet been adequately tested in people with progressive MS. Now the team proposes to test the mSMT in persons with progressive MS, measuring post-treatment changes on both laboratory measures of memory abilities and on daily life memory abilities, self-efficacy, quality of life, and occupational functioning.What does this mean for people living with progressive MS? The results may have a significant impact on addressing the troubling symptom of cognitive dysfunction and improving quality of life for people with progressive MS.
Title: Using patient-specific, iPSC-derived neurons to model neurodegeneration in multiple sclerosisPrincipal Investigator: David Pitt, M.D.Institution: Yale University School of MedicineAmount Awarded: €75,000Summary: Disease progression varies greatly among people with MS. The reason for this is unknown, but may be related to genetic differences in the susceptibility of nerve cells to injury. Glutamate is a compound that is normally found in the brain that can cause injury to neurons when it is present in excessive amounts. This team proposes to use neuron stem cells that have been derived from skin cells from individuals with MS to test if there are genetic differences in their neurons’ sensitivity to injury from glutamate. Several medications have been developed that modulate glutamate, and these could be potential new therapies for people with MS if it can be determined who may have glutamate sensitivity.What does this mean for people living with progressive MS? If some people are genetically predisposed to sensitivity to glutamate, this subset of individuals may benefit from therapies that address excessive glutamate to slow or stop disease progression.
Title: Miglustat as a therapy for secondary progressive multiple sclerosisPrincipal Investigator: Francisco Quintana, Ph.D.Institution: Brigham and Women's HospitalAmount Awarded: €75,000Summary: Astrocytes are cells in the brain that may play a destructive role in MS since among other activities, they are known to create scar tissue that may interfere with tissue repair. In the search for leads to new approaches to treating progressive MS, this team proposes to use an experimental mouse model that resembles several features of secondary-progressive MS to investigate the potential of a drug called miglustat. This drug is approved to treat other diseases, and it has been found to inhibit a protein, called “B4GALT6,” which the team found to be involved in the activation of astrocytes. The investigator proposes to test whether miglustat can inhibit astrocytes to stop disease progression. The team will also test its impact on human and mouse nerve cells isolated in the laboratory. What does this mean for people living with progressive MS? This study may point to a new strategy for stopping a key contributor to MS progression. Since miglustat is already is FDA-approved for other disorders, this would expedite its application to MS if it indeed proves safe and effective.
Title: Azetidine-induced oligodendrogliopathyPrincipal Investigator: Raymond Sobel, M.D.Institution: Stanford UniversityAmount Awarded: €75,000Summary: In MS, myelin, the fatty substance that surrounds and protects nerve fibers, is destroyed. Myelin is made by cells in the brain called oligodendrocytes. This team proposes to investigate one way that oligodendrocytes may be rendered susceptible to MS early in life. They are focusing on the effects of a compound found in sugar beets called Azetidine-2-carboxylic acid (Aze). Sugar beets are used in meat and dairy products and their geographical use resembles that of MS incidence. Aze resembles an amino acid called proline. Amino acids are the building blocks of proteins, and if Aze is mistakenly incorporated into proteins instead of proline, the resulting protein may be unstable. Previous studies have shown that when Aze is incorporated into proteins made by oligodendrocytes, the cells do not function normally. The team will investigate the possibility that when fed to rodents early in life, Aze is a dietary contributor to susceptibility to MS pathology. If Aze is shown to be harmful to oligodendrocytes, the results will establish a new, highly relevant rodent model of MS and suggest new research to explore this possible clue to an MS trigger.What does this mean for people living with progressive MS? If susceptibility to MS is due at least in part to exposure to a dietary component early in life, this will suggest ways to prevent and perhaps treat MS.
Title: Longitudinal multicenter cervical spinal tract diffusion MRI for progressive MSPrincipal Investigator: Junqian Xu, Ph.D.Institution: Mount Sinai School of MedicineAmount Awarded: €74,841Summary: Axons, also commonly known as nerve fibers, are the primary transmission lines of our nervous system. Destruction of axons during the course of MS has been found to be critically linked with long-term disability in people with progressive MS. Finding a way to accurately assess the stage and rate of axonal loss over time is key to developing new therapies that can protect or even regenerate axons to improve function. This team proposes to develop the infrastructure needed to facilitate clinical trials that track cervical spinal cord MRI measurements as a way of measuring the impact of potential therapies on MS damage and progression. The team proposes to use very high resolution cervical spinal cord MRI to study groups of people with progressive MS and controls without MS. This method will be used at two different sites and multiple times to ensure the quality of the findings.What does this mean for people living with progressive MS? Developing methods for tracking nervous system damage that occurs during MS progression is crucial for clinical trials that set out to determine the effectiveness of strategies at stopping or reversing this progression.