2019-2020 Research Update

Our mission is to fund cutting-edge, innovative research programs in our quest to find a cure for MS. Below are the 2019-2020 grantee research summaries from our newly awarded Young Investigators and Innovation Awards as well as updates from our second year Young Investigator grant awardees that began their basic science research in 2018.

First Year YI Grant Recipients

Assessing Arterial and Venous Vascular Markers in the Brain and Retina in Multiple Sclerosis

Marwa Kaisey, M.D., Assistant Professor, Department of Neurology – Cedars-Sinai

While new and effective treatments for multiple sclerosis continue to become available, we sorely lack novel, accurate tools to diagnose and track MS. Arteries and veins in the brain and the eye may show changes that help with MS diagnosis and disease activity; they also hold potential clues for understanding what causes MS and unearthing new treatment targets. We will investigate brain arterial vessel changes in MS. Research has demonstrated the key role of the brain’s blood vessels in perpetuating MS for decades. We also know that MS is more severe in patients with risk factors for diseases of the blood vessels that lead to heart attack and stroke. The small vessels themselves, however, have been difficult to investigate because, until recently, this required a brain biopsy or invasive angiography. We plan to use a non-invasive method, a new MRI technique, to investigate arterial markers that have not been defined in people with MS before.

The retina, an area in the back of the eye, is an easily visualized extension of the brain and central nervous system and so may be a practical tool to help diagnose MS and measure its activity. We will employ two non-invasive retinal photography techniques to visualize arteries at this interface between the eye and the brain.

Myelin-specific CD8+ T cell clonal analysis in MS

Joseph J. Sabatino, Jr., M.D./Ph.D., HS Clinical Instructor, Neurology – UCSF Weill Institute for Neurosciences

MS is an inflammatory demyelinating condition of the central nervous system (CNS) believed to be mediated by autoreactive immune cells.  Although largely overshadowed by CD4+ T cells and B cells, numerous lines of evidence suggest CD8+ T cells have a critical role in MS pathogenesis.  CD8+ T cells from MS lesions appear to express similar T cell receptors (TCRs), suggesting that they are expanded in response to an antigenic stimulus within the CNS.  Despite these observations, little is known about which antigens CD8+ T cells may be targeting in MS.  Myelin antigens are one such potential target, and we have recently demonstrated evidence of increased activation of myelin-specific CD8+ T cells in MS patients.

The goal of this project is to compare the TCR usage of myelin-specific CD8+ T cells of MS patients and control subjects.  In parallel, we will perform TCR sequencing analysis on total CD8+ T cell populations in the cerebrospinal fluid (CSF) and blood of the same individuals.  By comparing the CSF-derived TCR sequences with those of myelin-specific CD8+ T cells from the blood, we can determine if CD8+ T cells targeting myelin are present and expanded within the CSF of MS patients.  We believe this study will advance our understanding of which CD8+ T cells are involved in MS and potentially pave the way towards developing new biomarkers or therapeutic targets.

Leptomeningeal Enhancement in Multiple Sclerosis—A 7T MRI Study

Jonathan D. Zurawski, M.D., Associate Neurologist, Brigham & Women’s Hospital, Dept. of Neurology, Instructor of Neurology – Harvard Medical School

Leptomeningeal inflammation and associated cortical injury are novel findings in people with multiple sclerosis (MS) and may play a key role in the pathophysiology of disease progression. The detection of leptomeningeal enhancement (LME) by 7T MRI provides a promising new in vivo surrogate marker for such changes, potentially providing a non-invasive method to assess the risk of disease worsening. In this study, we aim to evaluate the prevalence, longitudinal change, associated tissue damage, and serum immunological correlates of LME using 7T MRI.

In a 2 year longitudinal study, we will evaluate the hypotheses that LME is associated with 1) MRI-defined cortical demyelination and cortical atrophy, 2) physical disability and cognitive impairment, and serum immune activation as assessed by miRNA profiling and lipid antibody activation. Ultimately, a better understanding of the factors leading to disease progression should lead to understanding disease heterogeneity and the identification of new therapeutic targets.

Second Year YI Grant Recipients

Bryostatin-1 as a potential modulator of the innate immune system in progressive multiple sclerosis

Michael Davin Kornberg, M.D., Ph.D., Assistant Professor of Neurology – Johns Hopkins

Progressive MS, which lacks satisfactory treatments, is characterized by chronic activation of so-called “innate” immune cells (macrophages and microglia) in the nervous system. These chronically activated innate immune cells cause ongoing injury and prevent repair processes such as remyelination, but no treatments targeting these cells have been developed. Our previous work has found that a brain-penetrant, naturally occurring drug called bryostatin-1 shows benefit in an animal model of MS by specifically targeting the innate immune system, differentiating it from current drugs and raising the possibility that it might be effective in progressive MS. We are currently conducting work to better understand how it works, along with whether it’s capable of suppressing innate immune cells within the brain and promoting remyelination.

Interactions between gut microbiome and B-cell depletion in MS

Erin Longbrake, M.D., Ph.D., Assistant Professor, Department of Neurology – Yale University

During the first year of the Young Investigator award, we developed our capacity for patient recruitment and made good progress towards enrolling newly diagnosed MS patients and obtaining serial specimens from patients initiating B-cell depletion. Additional studies to characterize bacterial metabolites of interest (e.g. short chain fatty acids) are underway. In Year 2 of the proposal, we will continue to recruit patients and will undertake multiple rounds of microbiome sequencing and metabolite characterization.

The gut microbiome is influential for the development of the immune system, and bacteria living in the gut are sensitive to changes in the environment (like obesity, low vitamin D, etc). The gut microbiome is also dysregulated by autoimmune diseases like MS.  Therefore, we think that the gut microbiome may be an important link connecting the altered MS immune system with environmental risk factors of the disease.

We also believe that MS medications depleting B-cells will have important effects on the gut microbiome and that this may be part of the reason these drugs are so effective in MS. My project is designed to identify what microbiome changes are induced by the medication. Future studies will then examine how these drug-induced changes impacts the disease.

Innovation Grant Recipients

Targeting Neurotoxic Glia to Promote Neuroprotection

Peter Calabresi, M.D., Professor of Neurology and Director of the Johns Hopkins MS Center

Multiple sclerosis is a major cause of non-traumatic progressive disability in young people. While we have several drugs to treat relapsing forms of the disease, there is an unmet need to prevent disability progression. In this application we propose to examine how certain brain cells called glia become activated in a way that cause damage to the myelin and nerves as occurs in people suffering from multiple sclerosis. Our team has discovered that a new drug, NLY01, may be especially effective at getting into the brain and suppressing the type of brain inflammation that we think causes damage to the nerve cells in people with MS. We have preliminary data that this drug suppresses the onset of brain inflammation in animals that is similar to what we see in people with multiple sclerosis. In this study we plan to treat the animals, after they are already diseased, to see if the new drug can suppress the ongoing brain inflammation and prevent nerve damage. These research lab studies will provide critical new information to scientists about inflammation in the brain causes damage, and will speed up the translation of this drug into clinical trials in people suffering with multiple sclerosis.

Retinal blood flow as a Biomarker in MS

Dennis Bourdette, M.D., FANA, FAAN, Professor of Neurology, School of Medicine – OHSU
In collaboration with David Huang M.D., Ph.D.

The eye as a window to the brain: Blood vessel damage in the brain and spinal cord is important to increasing neurodegeneration in MS. MS patients with vascular disease risk factors, such as high blood pressure and high cholesterol, have more disability. Previously, studies measuring blood flow in MS have relied on expensive and very difficult MRI techniques. Our study explores Optical Coherence Tomography Angiography (OCTA) as a new, fast, non-invasive test to measure blood flow changes in retina of the eye and we believe reflect similar changes in the brain.

Prior work shows that MS patients have decreased retinal blood flow on OCTA compared to healthy adults and that this blood

flow can improve over time. Our study seeks to explore these blood flow changes in the retina in patients with early MS and determine if these blood flow changes predict disease worsening. Our long-term goal is to use this pilot data to explore OCTA as an outcome measure to help develop neuroprotective therapies.

Defining the role of B cells in myelin-reactive T cell induction and maintenance

David A. Hafler, M.D., Professor of Neurology and Immunobiology, Chairman, Department of Neurology – Yale School of Medicine

Relapsing-remitting multiple sclerosis (MS) is a genetically-mediated, neuroinflammatory autoimmune disease characterized by inflammation in the brain and spinal cord. Immune cell recognizing brain proteins are thought to be critical mediators of this process and we have previously demonstrated that these brain reactive immune cells from patients with MS are inflamed, characterized by production of immune mediators that induce tissue destruction in the brain and spinal cord. This is different from healthy individuals without MS where the immune cells recognizing brain proteins secrete immune mediators that suppress inflammation. While these autoreactive immune cells are thought to be critical inciters of inflammation in the CNS of patients with the disease, the mechanism for the switch from anti-inflammatory to an inflamed state in MS is not known. It is critical to resolve both the unique pathogenic phenotype of autoreactive immune cells and the immunological networks promoting their dysfunction. Specifically, we will identify the antigen-presenting cells and cytokine producers that initially breach self-tolerance and supply signals to skew immune cell differentiation toward inflammatory subsets.

Evaluation of Hsp90-SF3B2 axis to prevent axonal degeneration in MS

Ahmet Hoke M.D., Ph.D. FRCPC, Professor, Neurology and Neuroscience, Director, Neuromuscular Division – Johns Hopkins School of Medicine

Secondary axonal degeneration remains one of the main challenges in multiple sclerosis (MS) with no effective therapies to prevent it. Although the exact mechanisms that lead to axonal degeneration in MS are unknown it is highly likely that they share some common molecular pathways involved in axonal degeneration seen in the peripheral nervous system. Recently we identified Hsp90-SF3B2 axis as an important player to prevent axon degeneration. We will be testing the relevance of this molecular axon protection pathway in vitro and in vivo using MS models. If successful, this opens up a new therapeutic target for MS.

Single cell analysis of the CNS oligovascular niche during demyelination and regeneration

Mark Petersen, M.D., Assistant Professor, Pediatrics, Neonatology Division – University of California San Francisco, Visiting Scientist – Gladstone Institutes

In MS, the nerve fibers in the brain and spinal cord lose their protective coating, called myelin, impairing the cell’s ability to transmit signals leading to problems with cognition, sensation, and movement. Myelin can be regenerated from stem cells that normally reside in the central nervous system in a process called remyelination; however, remyelination is blocked in MS leaving the brain unable to repair damaged myelin. If we understand why this repair mechanism is halted in the brain, we may be able to discover new treatments that promote recovery and stop the progression of MS. In previous efforts to promote brain repair in MS, scientists have focused on understanding what happens inside the cell. We have focused instead on the toxic proteins and inflammatory signals accumulating in the environment outside the cell. In MS, blood vessels in the brain become damaged which allows proteins from the blood to leak into the nervous system. We recently discovered that the blood clotting protein fibrinogen causes inflammation in the brain and blocks myelin repair. The goal of this project is to better understand how leaky blood vessels and fibrinogen block stem cells from repairing damaged myelin. This would open the possibility for new types of therapies to promote brain repair by targeting the inhibitory environment in the MS brain.

In this project, we will use a new microscope technique that allows us to see and specifically label cells around blood vessels in the living mouse brain. Using this technique in an MS animal model, we will label and isolate cells around leaky blood vessels in an area with myelin damage and compare them to the cells in an area of myelin repair. We will also determine whether genetically altered mice resistant to fibrinogen-induced inflammation are able to replace lost myelin better than normal mice. This research will provide basic information about the cell populations and inflammatory signals that block repair in MS and how the blood protein fibrinogen may contribute to MS disease progression. This could lead to new therapies to help patients with MS and many other diseases associated with myelin damage.

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