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    You are here : Home » MS Research News » Myelin Research

    Myelin Research

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    More news can be found in New Pathways Magazine, our bi-monthly publication, and also check daily at MSRC: Latest MS News.

    Mayo Clinic uses new approach to reverse multiple sclerosis in mice models

    Mouse studies in MSMayo Clinic researchers have successfully used smaller, folded DNA molecules to stimulate regeneration and repair of nerve coatings in mice that mimic multiple sclerosis (MS). They say the finding, published today in the journal PLoS ONE, suggests new possible therapies for MS patients.

    "The problem has been to find a way to encourage the nervous system to regenerate its own myelin (the coating on the nerves) so nerve cells can recover from an MS attack," says L. James Maher III, Ph.D., Mayo Clinic biochemist and senior author on the paper. "We show here that these small molecules, called aptamers, can stimulate repair in the mice we are studying."

    More than 2.5 million people have multiple sclerosis world-wide. There is no cure and no effective therapy to stop progression or repair damage to the myelin sheath that surrounds and protects the nerves. Without that protection, nerve fibres will be damaged, leading to declining mobility and cognitive function, and other debilitating complications.

    MS researchers, including Mayo neurologist Moses Rodriguez, M.D., a co-author on this paper, have focused on monoclonal antibodies in mice to stimulate myelin repair. The Rodriguez and Maher teams, working together, have determined that the aptamers are not only effective, but they are easy and cheap to synthesize -- an important point for drug developers. They also are stable and not likely to cause an immune response. This new approach must be validated in other mouse models to see if it might be a candidate for human clinical trials.

    The monoclonal antibodies used in earlier research are large and complex, but were shown to promote both cell signaling and remyelination of central nervous system lesions in mice. The aptamers used in this study are less than one-tenth the size of antibodies and are single-strands of DNA containing only 40 nucleotide units.

    The research was supported by Mayo Clinic and the National Multiple Sclerosis Society.

    Co-authors include Branislav Nastasijevic, Brent Wright, Ph.D., John Smestad, and Arthur Warrington, Ph.D., all of Mayo Clinic.

    Source: Eureka Alert! Copyright ©2012 by AAAS, the science society (29/06/12)

    The Myelin Repair Foundation achieves phase 1 myelin repair clinical trial

    Stem cellsThe Myelin Repair Foundation (MRF) today announced the achievement of a myelin repair Phase 1 clinical trial for multiple sclerosis earlier than the foundation's goal set for 2014. By establishing its Accelerated Research Collaboration (ARC) Model to advance myelin repair treatments forward into clinical trial Phase 1 within a decade, the Myelin Repair Foundation achieved this critical milestone ahead of its goal, validating the efficiency of the ARC model to speed drug development.

    This Phase 1 clinical trial conducted at Cleveland Clinic will examine the efficacy of a new myelin repair therapeutic pathway with mesenchymal stem cells (MSCs), based on MRF supported research conducted by MRF Principal Investigator Dr. Robert Miller, Professor of Neurosciences and Vice President for Research & Technology Management at Case Western Reserve University. To date, half of the 24 patients planned for this initial trial have been enrolled.

    "Scientists hope that one day their research will reach clinical trials, and I'm thrilled to achieve this milestone in my career," said Dr. Robert Miller. "Without the support of Myelin Repair Foundation funding a critical component of our research that is the basis of this trial, this achievement would not have been possible. Our partnership with the Myelin Repair Foundation has helped identify new pathways to treat disease that reverses damage, ultimately accomplishing so much more than the suppression of MS symptoms."

    Funded by the Myelin Repair Foundation, Dr. Miller's team of scientists identified an innovative clinical pathway through mesenchymal stem cell signals that not only protect myelin, which is damaged by the autoimmune reaction in MS, but also facilitates myelin repair. Current MS drugs on the market only focus on the suppression of the immune system to protect myelin from future damage; patients have no treatment options available to repair myelin once damage occurs in MS.

    "Our goal to support research that would enter Phase 1 trials within a decade was deemed nearly impossible," said Scott Johnson, president and CEO of the Myelin Repair Foundation. "To think we achieved this ambitious goal even earlier than we planned illustrates the effectiveness of our innovative research model that accelerates promising scientific discoveries into clinical trials. Even with this success, we refuse to rest on our laurels and will continue to progress myelin research into multiple clinical trials. We remain focused on our singular goal: To speed the development of an effective myelin repair treatment to reach patients with multiple sclerosis."

    For more information about the clinical trial and enrollment, please visit .

    About the Myelin Repair Foundation

    The Myelin Repair Foundation (MRF) is a Silicon Valley-based, non-profit research organization focused on accelerating the discovery and development of myelin repair therapeutics for multiple sclerosis. Its Accelerated Research Collaboration(TM) (ARC(TM)) model is designed to optimize the entire process of medical research, drug development and the delivery of patient treatments.

    Source: MarketWatch Copyright © 2012 MarketWatch, Inc (15/06/12

    Myelin Repair Foundation research fosters clinical trial for Multiple Sclerosis

    MyelinThe Myelin Repair Foundation (MRF) announced today that its research might soon lead into a clinical proof-of-concept trial at the Department of Neuroimmunology and Multiple Sclerosis Research (nims), University Hospital Zurich, Switzerland, and the Institute for Neuroimmunology and Clinical Multiple Sclerosis Research (inims) in Hamburg, Germany.

    This clinical trial will determine the safety and efficacy of a potential therapeutic pathway to desensitize the immune system to myelin in multiple sclerosis (MS) patients, based on research conducted by MRF Investigator Dr. Stephen D. Miller from Northwestern University Feinberg School of Medicine.

    Such proof-of-concept clinical trial will be headed by Dr. Roland Martin, head of the Dept. of Neuroimmunology and MS Research in Zurich. Phase 1 is already underway.

    "The Myelin Repair Foundation has established a solid scientific foundation to initiate this clinical trial that examines a potential targeted treatment pathway for MS patients, the first of its kind," said Dr. Roland Martin, head of the Dept. of Neuroimmunology and MS Research in Zurich and former director of inims. "I am excited to lead MRF research into this clinical trial, which will examine the potential of a treatment specifically targeted to re-establish tolerance of myelin during the earliest stages of MS."

    "I am thrilled that the scientific discoveries from my lab could impact MS patients all over the world," said MRF Investigator Dr. Stephen D. Miller, professor in microbiology-immunology at Northwestern's Feinberg School. "The Myelin Repair Foundation's support and unique research approach which facilitates collaboration with other leading neuroscientists supported by the MRF has sped up the research process to where we are today, moving an MS therapeutic closer to the patient with this clinical trial."

    By inducing immune tolerance to myelin, a hospitable environment for myelin repair in MS patients is facilitated through two primary mechanisms: halting immune-mediated damage thus protecting myelin and minimizing the risk of infection, a frequent side effect of current MS therapeutics. This clinical trial will examine an antigen-specific MS therapy, a superior alternative to the non-discriminating immunosuppressive treatment regimen used currently for MS.

    "We are proud to be working with Dr. Roland Martin at the helm advancing this clinical trial," said Scott Johnson, president of the Myelin Repair Foundation. "By supporting Dr. Stephen Miller's scientific discoveries, MRF moves closer to halting the progression of the myelin degeneration of this disease, with possible broader implications for patients of all autoimmune diseases."

    About the University Hospital Zurich, Department of Neuroimmunology and Multiple Sclerosis Research

    The Department of Neuroimmunology and MS Research (nims) at the Neurology Clinic and the University Hospital Zurich focuses on basic disease mechanisms of MS, biomarkers and disease heterogeneity, and develops novel treatments for all stages and forms of MS. It collaborates with inims, Hamburg, where similar objectives are pursued.

    About the University Medical Center Hamburg Eppendorf, Institute for Neuroimmunology and Clinical MS Research

    The Institute for Neuroimmunology and Clinical MS Research (inims) at the Medical Center Hamburg-Eppendorf (UKE) integrates a basic science institute with a MS MRI unit and a dedicated outpatient clinic and day hospital that regularly provides all levels of care for approximately 1200 patients. Inims has had greater 3000 patient contacts last year, and besides basic and clinical research, a particular focus is directed at developing novel therapies for MS.

    About the Myelin Repair Foundation

    The Myelin Repair Foundation (MRF) is a Silicon Valley-based, non-profit research organization focused on accelerating the discovery and development of myelin repair therapeutics for multiple sclerosis. Its Accelerated Research Collaboration(TM) (ARC(TM)) model is designed to optimize the entire process of medical research, drug development and the delivery of patient treatments.

    Source: Market Watch Copyright © 2012 MarketWatch, Inc (07/03/12)

    Multiple sclerosis: damaged myelin not the trigger?

    Myelin Damaged myelin in the brain and spinal cord does not cause the autoimmune disease Multiple sclerosis (MS), neuroimmunologists from the University of Zurich have now demonstrated in collaboration with researchers from Berlin, Leipzig, Mainz and Munich.

    In the current issue of Nature Neuroscience, they therefore rule out a popular hypothesis on the origins of MS. The scientists are now primarily looking for the cause of the development of MS in the immune system instead of the central nervous system.

    Millions of adults suffer from the incurable disease multiple sclerosis (MS). It is relatively certain that MS is an autoimmune disease in which the body’s own defense cells attack the myelin in the brain and spinal cord. Myelin enwraps the nerve cells and is important for their function of transmitting stimuli as electrical signals. There are numerous unconfirmed hypotheses on the development of MS, one of which has now been refuted by the neuroimmunologists in their current research: The death of oligodendrocytes, as the cells that produce the myelin sheath are called, does not trigger MS.

    Neurodegenerative hypothesis obsolete
    With their research, the scientists disprove the so-called “neurodegenerative hypothesis”, which was based on observations that certain patients exhibited characteristic myelin damage without a discernable immune attack. In the popular hypothesis, the scientists assume that MS-triggering myelin damage occurs without the involvement of the immune system. In this scenario, the immune response against myelin would be the result – and not the cause – of this pathogenic process.

    The aim of the research project was to confirm or disprove this hypothesis based on a new mouse model. Using genetic tricks, they induced myelin defects without alerting the immune defense. “At the beginning of our study, we found myelin damage that strongly resembled the previous observations in MS patients,” explains Burkhard Becher, a professor at the University of Zurich. “However, not once were we able to observe an MS-like autoimmune disease.” In order to ascertain whether an active immune defense causes the disease based on a combination of an infection and myelin damage, the researchers conducted a variety of further experiments – without success. “We were unable to detect an MS-like disease – no matter how intensely we stimulated the immune system," says Ari Waisman, a professor from the University Medical Center Mainz. “We therefore consider the neurodegenerative hypothesis obsolete.”

    Focus on immune system
    The teams involved in the study want to continue researching the cause and origins of MS. “In light of these and other new findings, research on the pathogenesis of MS is bound to concentrate less on the brain and more on the immune system in future,” says Professor Thorsten Buch from the Technischen Universität München.

    Giuseppe Locatelli, Simone Wörtge, Thorsten Buch, Barbara Ingold, Friederike Frommer, Bettina Sobottka, Martin Krueger, Khalad Karram, Claudia Bühlmann, Ingo Bechmann, Frank L. Heppner, Ari Waisman and Burkhard Becher. Primary oligodendrocyte death does not elicit anti-CNS immunity. Nature Neuroscience. 26 February, 2012. Doi: 10.1038/nn.3062

    Source: Health (27/02/12)

    Collaboration to develop myelin regenerative compounds for MS treatment

    MyelinThe Myelin Repair Foundation (MRF) and ENDECE Neural, LLC have formed a partnership to expedite the advancement of myelin regeneration drug candidates for Multiple Sclerosis (MS) patients through pre-clinical studies and into Phase I clinical studies.

    Through this unique collaboration, the newly launched MRF Translational Medicine Center will assess the myelin regenerating capabilities of proprietary small molecule compounds from ENDECE Neural in novel MRF Multiple Sclerosis models for their effectiveness in reversing myelin damage.

    These ENDECE Neural compounds will be evaluated at the MRF Translational Medicine Center, which is dedicated to the acceleration of the drug discovery and development process for new MS treatments. This laboratory facility offers a rigorous, industry-leading translational medicine platform, led by MRF personnel with over four decades of extensive biopharma experience moving therapeutic compounds into clinical trials. The goal of the MRF Translational Medicine Center is to advance potential myelin repair treatment targets toward commercialization to benefit MS patients.

    "By combining the innovative approach by ENDECE Neural to remyelination and the resources available at the MRF Translational Medicine Center, we can expedite progress towards developing new MS treatments for patients," says Dr. Jay Tung, Ph.D., Vice President of Drug Discovery and Research Operations at MRF. "We are excited to work with ENDECE Neural since we both share a deep commitment to bringing novel therapeutics to MS patients who simply cannot wait for new cures."

    "We approached the Myelin Repair Foundation about joining forces because of their expertise in myelin repair models, in addition to their new in-house capabilities at the MRF Translational Medicine Center," says Dr. James Yarger, Ph.D., President of ENDECE Neural. "Unlike current MS therapies, which target immune response and inflammation to slow relapses, our drug compounds are promising candidates for remyelination, with the potential to restore muscle control and mobility. Without remyelination, there can be no cure for MS," states Dr. Yarger.

    About the Myelin Repair Foundation

    The Myelin Repair Foundation is a Silicon Valley-based, non-profit research organization focused on accelerating the discovery and development of myelin repair therapeutics for Multiple Sclerosis. Its Accelerated Research Collaboration(TM) (ARC(TM)) model is designed to optimize the process of medical research, drug development and the delivery of new patient treatments.

    About ENDECE Neural, LLC

    ENDECE Neural, LLC is the privately held neurological drug development subsidiary of ENDECE, a biopharmaceutical company located in Wisconsin. As a small molecule drug discovery business, ENDECE was founded on the premise that the ability to control multiple genes within signaling pathways would create opportunities for treating diseases with largely unmet medical needs, including neurodegenerative diseases, cancer, and pain. ENDECE has several late pre-clinical stage programs, including therapeutics for Multiple Sclerosis (ENDECE Neural, LLC) and Cancer (ENDECE Oncology, LLC). The Intellectual Property (IP) surrounding the portfolio of small molecule compounds owned and developed by ENDECE is protected by six composition of matter and use patents; the first has been issued. The management team of ENDECE has previously taken multiple drug candidates from laboratory discovery, through clinical studies, and the FDA approval process to commercial launch.

    Source: Myelin Repair Foundation; ENDECE Neural, LLC (09/02/12)

    Study finds age-related effects in MS may be reversible

    MyelinScientists at Joslin Diabetes Center, Harvard University, and the University of Cambridge have found that the age-related impairment of the body’s ability to replace protective myelin sheaths, which normally surround nerve fibers and allow them to send signals properly, may be reversible, offering new hope that therapeutic strategies aimed at restoring efficient regeneration can be effective in the central nervous system throughout life.

    In a proof-of-principle study published in the journal Cell Stem Cell, the researchers report that defects in the regeneration of the myelin sheaths surrounding nerves, which are lost in diseases such as multiple sclerosis may be at least partially corrected following exposure of an old animal to the circulatory system of a young animal. Myelin is a fatty substance that protects nerves and aids in the quick transmission of signals between nerve cells.

    Using a surgical technique, the researchers introduced an experimental demyelinating injury in the spinal cord of an old mouse, creating small areas of myelin loss, and then exposed those areas to cells found the blood of a young mouse. By doing so, they found that the influx of certain immune cells, called macrophages, from the young mouse helped resident stem cells restore effective remyelination in the old mouse’s spinal cord. This “rejuvenating” effect of young immune cells was mediated in part by the greater efficiency of the young cells in clearing away myelin debris created by the demyelinating injury. Prior studies have shown that this debris impedes the regeneration of myelin.

    “Aging impairs regenerative potential in the central nervous system,” says author Amy J. Wagers, PhD, an associate professor of stem cell and regenerative biology at Harvard University and Joslin, who co-led the study with Professor Robin Franklin, director of the MS Society’s Cambridge Centre for Myelin Repair at the University of Cambridge. “This impairment can be reversed, however, suggesting that the eventual development of cell-based or drug-based interventions that mimic the rejuvenation signals found in our study could be used therapeutically.”

    This could be particularly useful, she adds, in treating MS, which typically spans many decades of life, and thus is likely to be influenced by age-dependent reductions in the ability of myelin to regenerate. In MS, the body’s own immune system attacks the myelin sheath and prevents nerve fibers in the brain from sending signals properly, which can cause mild symptoms such as limb numbness or more serious ones like losing the ability to walk or speak. As people with MS age, remyelination decreases significantly, eventually causing permanent loss of nerve fibers.

    “For MS sufferers,” says Franklin, “this means that, in theory, regenerative therapies will work throughout the duration of the disease. Specifically, it means that remyelination therapies do not need to be based on stem cell transplantation since the stem cells already present in the brain and spinal cord can be made to regenerate myelin, regardless of a person’s age.”

    Other Joslin co-authors of the study were Tata Nageswara Rao and Jennifer L. Shadrach.

    Source: Newswise ©2012 Newswise, Inc (06/01/12)

    Diabetic mice provide a surprising breakthrough for MS research

    MouseIn humans, active periods of the debilitating disease Multiple Sclerosis (MS) can last for mere minutes or extend to weeks at a time. They're caused by lesions in the brain that develop, partly heal, and then recur.

    Research into a cure has been difficult, because to date scientists have not been able to replicate these brain recurring symptoms in laboratory mice. That's frustrating because these lab animals, known as animal "models," are the primary tool for research into the mechanisms and potential treatments for MS.

    But now, by using a mouse model for diabetes instead, Dr. Dan Frenkel of Tel Aviv University's Department of Neurobiology, working alongside Prof. Yaniv Assaf and Ph.D. student Hilit Levy, may provide a surprising breakthrough for research into a cure for MS.

    The team has discovered that when mice with Type 1 Diabetes are injected with myelin protein — the insulating material that coats neurons — they experience the periods of relapsing and remitting disability associated with brain lesions in humans. And for the first time, they've been able to monitor this brain lesion process using magnetic resonance imaging.

    Dr. Frenkel believes his finding will lead to the development of more effective treatments for MS. This research has been published in Experimental Neurology.

    Tracking lesions in the brain
    MS, an autoimmune disease in which the immune system attacks in the brain and inhibits the transfer of signals between neurons, often leads to devastating disabilities such as blindness and paralysis. From its onset, the disease attacks in peaks which become increasingly more severe until patients are permanently disabled.

    Traditionally, mouse model populations for MS research have been created by injecting mice with myelin protein emulsified in bacteria. With the addition of bacteria, the immune system mobilizes against the myelin, creating an MS-like autoimmune response. However, the disease does not present in this model as it does in human sufferers — most mouse models experience a single inflammatory peak which leaves them with permanent symptoms such paralysis of the legs. The damage can be detected in the spinal cord, but not in the brain.

    "We discovered that when we gave them the same myelin protein injection, a mouse model that develops Type 1 Diabetes will instead exhibit peaks of inflammatory responses similar to those of chronic progressive MS, which relapses and remits," Dr. Frenkel says. The mice also suffer from brain lesions in addition to spinal cord damage, making them a more viable model for studying and developing treatment for MS in humans.

    Using a special MRI machine for imaging small animals, the researchers followed each mouse model over the course of several months, noting the activity of the brain and the development of lesions corresponding to peaks of inflammation. The lesions and the inflammation in the brain can be followed in the same way within these animals as in a human with MS, says Dr. Frenkel. "Now, we can follow the different stages that occur after the autoimmune response is already triggered, and look for different targets that will not only help to enhance recovery, but prevent further damage as well."

    Turning temporary recovery into permanent repair
    Currently, all FDA approved drugs on the market to treat MS were developed using traditional mouse models. Their focus is to delay the clinical signs of the disease caused by autoimmunity, lengthening the time between attacks. So far, this method has led to a temporary fix, but not a cure. With his alternative mouse model, Dr. Frenkel says, researchers can gather more information on how the brain heals after an attack, and start to develop treatment options that mimic this natural recovery process — turning temporary recovery into permanent repair.

    "With the use of magnetic resonance imaging, we can follow the brain lesions within the mouse model, and characterize the process of relapsing," Dr. Frenkel says. They have already begun to develop treatments with initial success. “We are looking at ways to encourage the glia cells — cells in the brain that support the neurons — to promote brain repair," he says.

    Source: Medical Xpress © Medical Xpress 2011-2012 (05/01/12)

    MS cognitive research yields myelin repair surprise

    MyelinBy taking a different approach, researchers have discovered what could eventually be a new type of treatment.

    Sometimes in scientific research, taking a new angle can unearth unexpected but welcome discoveries. And that’s what happened when researchers in University College Dublin’s Conway Institute looked at a type of tissue damage associated with multiple sclerosis.

    It’s early days yet, but by analysing the effects of a cognition-enhancing agent on nerve cells in the lab, they have identified what could eventually offer a new approach to help address the condition.

    In MS, a progressive neurologic condition that affects more than 7,000 people in Ireland and 2.5 Million world-wide, it’s thought the immune system attacks an insulating, fatty sheath around nerve cells called myelin, explains researcher Dr Mark Pickering, a post-doc at UCD’s school of biomolecular and biomedical science.

    When myelin is damaged, the nerves can no longer work properly, and therapies try to protect the remaining, intact myelin rather than targeting the myelin which has already been damaged, according to Pickering.

    “So far, drugs that have been used to treat MS are looking at preventing the immune damage to myelin,” he says.

    In his own studies, Pickering was looking at links between damage to myelin and cognition, or the ability of the brain to function in learning. And while working with a type of drug that can enhance cognition, he discovered that it also had a welcome talent for prompting the repair of damaged myelin in cells growing in the lab.

    “The project wasn’t initially to look at the myelin itself, it was to look at cognition, a secondary effect of the loss of myelin,” he recalls. “But we found that treatment with this drug accelerated the repair of myelin.”

    The work, which was funded by the MS Society of Ireland, used neurons or nerve cells growing in a dish.

    Pickering treated the neurons with a toxin that damages the myelin surrounding the neurons, and then he looked at the effects of adding this cognition-enhancing drug.

    Neurons without the added drug repaired the myelin slowly over several days, but if the drug was added the myelin repair was dramatically faster, says fellow researcher Dr Keith Murphy, a principle investigator at the neurotherapeutics research group in UCD.

    “At 24 hours after the toxin was removed, the myelin around the neurons is still very depleted in the normal situation, whereas if you had added the cognition-enhancing drug the myelin is completely normal at that point,” he explains.

    “The amount of myelin left after the toxin alone would be 20 per cent of healthy levels, but with the drug on board it is back up to normal.” The cognition-enhancing drug also appears to accelerate myelin repair in other pre-clinical models where myelin has been damaged, according to the researchers.

    So to build on their initial findings, the team now has funding from Enterprise Ireland and the Congressionally Directed Medical Research Programs in the US to take the project further.

    They plan to do more pre-clinical studies with the drug, and then progress to the first human trials, according to Murphy.

    “We are hoping that we will be ready to start to think about clinical trials within a two-year period if the data keep looking positive,” he says.

    And ultimately, if all goes to plan, how would they see a myelin-repair agent being used?

    “To put it into its disease context, the most usual form of MS is the relapsing-remitting version, where there are periods of inflammation causing the damage, then the inflammation dies down and there’s a period of repair of the myelin. The symptoms more or less resolve themselves in the remission period,” says Murphy.

    He describes how a drug treatment to boost myelin repair could theoretically be used during those times of remission, to help tackle the damage caused during the relapsing, inflammatory periods.

    “Current treatments for MS elongate the periods of remission – so you could use those drugs to buy the time, elongate the remission period, and at the same time use a myelin repair-boosting agent to make sure that the damage doesn’t progressively get worse over time.”

    The researchers are keen not to raise false hopes, but they are optimistic that because the drug has previously been proven safe in humans, and because it could be trialled within the context of existing treatments for MS, they should know within about five years whether the approach can help.

    The drug’s effect on myelin was something they hadn’t suspected at the start, but which they welcomed when they found it, says Murphy.

    Source: © 2011 (01/11/11)

    Brain electrical activity spurs insulation of brain’s wiring

    MyelinNIH study identifies trigger that speeds brain cell communication

    Researchers at the National Institutes of Health have discovered in mice a molecular trigger that initiates myelination, the process by which brain cell networks are reinforced with an insulating material called myelin that speeds their ability to transmit messages.

    The myelination process is an essential part of brain development. Myelin formation is necessary for brain cells to communicate and it may contribute to development of skills and learning.

    The researchers showed that an electrical signal passing through a brain cell (neuron) results in the brain cell releasing the molecule glutamate. Glutamate, in turn, triggers another type of brain cell, called an oligodendrocyte, to form a point of contact with the neuron. Signals transmitted through this contact point stimulate the oligodendrocyte to make myelin protein and begin the process of myelination. In this process, the oligodendrocyte wraps myelin around axons— the long, cable-like projections that extend from each neuron. The myelination process is analogous to wrapping electrical tape around bare wires.

    Electrical signals transmitted from one neuron to the next are a basic form of communication in the brain. The myelin layers that oligodendrocytes wrap around neurons boost these signals so that they travel 50 times faster than before.

    The study was conducted by Hiroaki Wake, Philip R. Lee, and R. Douglas Fields of the Nervous System Development and Plasticity Section of the NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). Their findings appear online in Science Express.

    “Insulation begins to form on axons in the late stages of fetal development, but the process continues through childhood, adolescence, and into early adulthood,” said Dr. Fields, the study’s senior author. “For example, infants cannot hold up their heads or walk until the appropriate motor axons become myelinated, and the frontal lobes of the brain, responsible for judgment and higher-level complex reasoning, are not fully myelinated until the early twenties.”

    Understanding how oligodendrocytes generate and help repair myelin could provide insight into how only the appropriate axons in the brain become insulated during development as people acquire skills, with the eventual goal of helping them do so more efficiently, Dr. Fields explained. Similarly, understanding the myelination process could lead to insights into disorders like multiple sclerosis, in which myelin is either damaged or destroyed. Moreover, understanding myelination may allow researchers to speed myelination— and repair— of axons recovering from injury.

    Throughout the brain, oligodendrocytes and neurons exist side by side. The researchers placed mouse nerve cells and myelin-making oligodendrocytes together in a dish and stimulated the nerve cells with electrical pulses. After three weeks, they found that the nerve cells were wrapped in a myelin covering.

    In a separate culture of neurons and oligodendrocytes, the researchers blocked the release of the molecule glutamate, a neurotransmitter. Neurotransmitters make it possible for signals to pass between cells. When glutamate release was blocked, very little myelin coating formed. Further experiments showed that after the electrical pulses and the release of glutamate, nerve cells and the neighboring oligodendrocytes began sending chemical signals back and forth. Then the oligodendrocytes started to make the protein used to form the myelin sheath. Specifically, receptors on the cell membrane of oligodendrocytes detect glutamate released by the axon, and this triggers the formation of what the researchers termed specialized adhesive signaling junctions—points of contact between oligodendrocytes and axons that enable signals to be passed between the cells. Then the oligodentrocytes began depositing myelin on electrically active axons, but not on axons that were not electrically active.

    “This shows that axons that are transmitting electrical signals will become preferentially insulated by myelin,” Dr. Fields said.

    Source: National Institutes of Health (NIH) (12/08/11)

    Myelin influences how brain cells send signals

    MyelinThe development of a new cell-culture system that mimics how specific nerve cell fibers in the brain become coated with protective myelin opens up new avenues of research about multiple sclerosis. Initial findings suggest that myelin regulates a key protein involved in sending long-distance signals.

    Multiple sclerosis (MS) is an autoimmune disease characterized by damage to the myelin sheath surrounding nerve fibers. The cause remains unknown, and it is a chronic illness affecting the central nervous system that has no cure.

    MS has long been considered a disease of white matter, a reference to the white-colored bundles of myelin-coated axons that project from the main body of a brain cell. But researchers have discovered that the condition also affects myelinated axons scattered in gray matter that contains main bodies of brain cells, and specifically the hippocampus region, which is important for learning and memory.

    Up to half of MS patients suffer cognitive deficits in addition to physical symptoms. Researchers suspect that cognitive problems are caused by abnormal electrical activities of the demyelinated axons extending from hippocampal cells, but until now have not been able to test myelin's role in this part of the brain.

    Ohio State University researchers have created a system in which two types of cells interact in a dish as they do in nature: neurons from the hippocampus and other brain cells, called oligodendrocytes, whose role is to wrap myelin around the axons.

    Now that the researchers can study how myelination is switched on and off for hippocampal neurons, they also can see how myelin does more than provide insulation – it also has a role in controlling nerve impulses traveling between distant parts of the nervous system. Identifying this mechanism when myelin is present will help improve understanding of what happens when axons in this critical area of the brain lose myelin as a result of MS, researchers say.

    So far, the scientists have used the system to show that myelin regulates the placement and activity of a key protein, called a Kv1.2 voltage-gated potassium channel, that is needed to maintain ideal conditions for the effective transmission of electrical signals along these hippocampal axons.

    "This channel is important because it is what leads to electrical activity and how neurons communicate with each other downstream," said Chen Gu, assistant professor of neuroscience at Ohio State and lead author of the study. "If that process is disrupted by demyelination, disease symptoms may occur."

    The study appears in the current (July 22, 2011) issue of the Journal of Biological Chemistry.

    To create the cell culture system, the researchers began with hippocampus neurons from a rodent brain – a cell type that Gu has worked with for years. In culture, these cells can grow and develop dendrites – other branch-like projections off of neurons – and axons as well as generate electrical activity and synaptic connections, the same events that occur in the brain.

    The researchers then added oligodendrocytes, along with some of their precursor cells, to the same dish as the neurons. And eventually, after maturing, these oligodendrocytes began to wrap myelin around the axons of the hippocampal neurons.

    This system takes about five weeks to create, but the trickiest part, Gu said, was developing the proper solution for this culture so that both kinds of cells would behave as nature intended.

    "In the end, the composition of the culture medium is basically half from a solution that supports the neurons and half from a medium in which the oligodendrocytes function well. We know that all the cells were happy because we got myelin," said Gu, also an investigator in Ohio State's Center for Molecular Neurobiology.

    With the system established, they then turned to experimentation to test the effects of the myelin's presence on these specific brain cells.

    Nerve cells send their signals encoded in electrical impulses over long distances. Concerted actions of various ion channels are required for properly generating these nerve impulses. Potassium channels are involved at the late phase in an impulse, and its role is to return a nerve cell to a resting state after the impulse has passed through it and gear up for the next one. The Kv1.2 ion channel helps ensure that this process works smoothly.

    By experimentally manipulating signal conditions with the new co-culture system, Gu and his colleague were able to establish part of the sequence of events required for myelinated hippocampal neurons to effectively get their signals to their targets. Starting with a protein known to be produced by myelin and axons, called TAG-1, a cell adhesion molecule, they traced a series of chemical reactions indicating that myelin on the hippocampal axons was controlling the placement and activity of the Kv1.2 ion channel.

    "The analysis allowed us to see the signaling pathways involving myelin's regulation of the Kv1.2 channel's placement along the axon as well as fine-tuning of the channel's activity," Gu said.

    When MS demyelinates these axons, the affected nerve cells don't get the message to rest, and subsequently can't prepare adequately to receive and transmit the next signal that comes along.

    "This means a nerve impulse will have a hard time traveling through the demyelinated region," Gu said. "This shows that the ion channel is probably involved in the downstream disease progression of MS."

    Gu envisions many additional uses for the new co-culture system, including additional studies of how myelin affects the behavior of other channels, proteins and molecules that function within axons, as well as to screen the effects of experimental drugs on these myelinated cells.

    This work was supported by a Career Transition Fellowship Award from the National Multiple Sclerosis Society and a grant from the National Institute for Neurological Disorders and Stroke.

    Source: ©™ 2003-2011 (22/07/11)

    Potential novel approach for promoting remyelination and inhibiting autoimmune activation identified

    DR6Biogen Idec announced results from a study that suggest that inhibiting death receptor-6 (DR6) function may represent a novel approach in the treatment of multiple sclerosis by blocking autoimmune response while promoting remyelination. Data from in vitro and in vivo models were published online today and will be published in the July print issue of Nature Medicine.

    "Our approach to finding new treatments for this complex disease looks beyond known pathways affected by current MS treatments," said Sha Mi, Ph.D., distinguished investigator, neurobiology research, Biogen Idec. "Our in vivo and in vitro studies demonstrate that inhibiting or blocking DR6 function results in robust axonal remyelination. These data provide strong evidence that this targeted approach warrants further research and ultimately may lead to an important new way of treating demyelinating diseases, including MS."

    MS affects each person differently, and more treatment options that target multiple pathways are needed in order to meet the various needs of patients. This study is the first-ever to demonstrate the negative role that DR6 plays in regulating remyelination within the central nervous system. Equally important, the data support the development of DR6 antagonist as a treatment for MS, a neurodegenerative disease that contains both autoimmune and demyelination components. The dual role of DR6 antagonists in promoting remyelination and inhibiting autoimmune activation represents a novel approach for the treatment of multiple sclerosis and other central nervous system diseases that result from demyelination.

    "Until we find a cure, Biogen Idec is dedicated to driving ground-breaking research and pursuing highly differentiated therapies for the treatment and management of MS and other central nervous system diseases," said Douglas E. Williams, executive vice president, research & development, Biogen Idec. "No currently approved MS treatment targets DR6, and the identification of the potential role of this receptor illustrates the breadth of our ongoing commitment to using cutting-edge science to discover of potential new treatment options for the MS community."

    Source: Biogen Idec (04/07/11)

    New discovery could aid remyelination in Multiple Sclerosis

    MyelinResearchers believe they may have found a "missing link" in the treatment of multiple sclerosis (MS).

    Scientists said they have discovered a new molecule, XAV939, that could lead to a drug treatment to repair the damage caused by the disease.

    The molecule is able to stimulate stem cells to repair myelin, the fatty material that coats and insulates nerves.

    Damage to myelin can cause the symptoms of MS but there are currently no treatments to repair it.

    The study, published in Nature Neuroscience, was carried out by scientists at the University of California San Francisco and the University of Cambridge, and funded by the MS societies of the US and UK.

    Robin Franklin, Professor of Neuroscience at Cambridge and co-author of the study, said: "There are currently no treatments that repair damage to myelin caused by MS, which is a missing link in the treatment of the condition.

    "This discovery means we now have even more credible opportunities to promote myelin repair, which is a really promising step forward.

    "Our efforts will now be focused on translating these findings into treatments for people with MS."


    Permanent damage to white matter tracts, comprising axons and myelinating oligodendrocytes, is an important component of brain injuries of the newborn that cause cerebral palsy and cognitive disabilities, as well as multiple sclerosis in adults.

    However, regulatory factors relevant in human developmental myelin disorders and in myelin regeneration are unclear.

    We found that AXIN2 was expressed in immature oligodendrocyte progenitor cells (OLPs) in white matter lesions of human newborns with neonatal hypoxic-ischemic and gliotic brain damage, as well as in active multiple sclerosis lesions in adults. Axin2 is a target of Wnt transcriptional activation that negatively feeds back on the pathway, promoting β-catenin degradation. We found that Axin2 function was essential for normal kinetics of remyelination.

    The small molecule inhibitor XAV939, which targets the enzymatic activity of tankyrase, acted to stabilize Axin2 levels in OLPs from brain and spinal cord and accelerated their differentiation and myelination after hypoxic and demyelinating injury.

    Together, these findings indicate that Axin2 is an essential regulator of remyelination and that it might serve as a pharmacological checkpoint in this process.

    Stephen P J Fancy, Emily P Harrington, Tracy J Yuen, John C Silbereis, Chao Zhao, Sergio E Baranzini, Charlotte C Bruce, Jose J Otero, Eric J Huang, Roel Nusse, Robin J M Franklin & David H Rowitch

    Axin2 as regulatory and therapeutic target in newborn brain injury and remyelination

    Source: Eveing Standard © 2011 ES London Limited & Nature Neuroscience © 2011 Nature Publishing Group (27/06/11)

    Scientists probe strategies to repair neuron damage in MS

    MyelinScientists working collaboratively around the world say they are coming closer to developing therapies that may help restore neurologic function in patients with multiple sclerosis (MS). However, they caution that such therapies are only beginning to enter early clinical trials and may be years from the clinic.

    Most existing therapies for MS aim to tamp down aberrant immune function and are especially helpful for some phases of the disease, although patients may still progress to a chronic, more progressive stage of illness. In addition, some newer therapies aim to reduce specific symptoms of the disorder. For example, the US Food and Drug Administration recently approved dextromethorphan hydrobromide and quinidine sulfate to treat pseudobulbar affect, a condition marked by uncontrolled emotional outbursts that may develop in patients with MS or certain other neurologic disorders.

    Now, several groups of scientists and MS organizations have reported that they have developed sufficient evidence from animal- and tissue-based studies to begin safety trials of agents that may help to restore some function in patients who have experienced neurologic impairments from MS. Among the key therapies under study are agents that may help remyelinate damaged neurons, including one that is now in human safety trials, and stem cell–based therapies that may help promote endogenous neural repair.

    In January, the US National Multiple Sclerosis Society in New York convened a meeting of 4 teams of researchers, representing numerous institutions around the world, to report on their research on restorative strategies for MS. The society has spent $5 million over 5 years to fund efforts by the teams to identify targets for neuroprotective therapies, to develop tools for documenting the effects of such therapies, and to design a trial. During a webcast at the end of the meeting, the researchers reported that the studies so far indicate that repair is possible and that enough basic evidence has accumulated to begin preliminary clinical trials

    “There is always hope,” said Peter Calabresi, MD, director of the Johns Hopkins MS Center in Baltimore during the webcast. “In terms of repair, in the last 5 years we’ve learned that there is lots of potential.”


    The past decade has seen tremendous progress in understanding the molecular mechanisms and pathways involved in the neural damage that accumulates in patients with MS, explained Timothy Coetzee, PhD, chief research officer of the National MS Society.

    “We’ve seen an explosion in understanding about the damage that's happening,” he said.

    But moving that basic science into the clinical realm has been a challenge. In fact, Coetzee noted, as recently as 2002, it was unimaginable to anticipate starting clinical trials. However, efforts by the National MS Society, its counterpart in the United Kingdom, the Myelin Repair Foundation in Saratoga, Calif, and other similar groups, as well as collaborations among them, have helped push the work forward. “We are all agreed on the same end goal,” he said.

    Researchers from one of the teams funded by National MS Society recently published results from studies in rats and mice that suggest the retinoid acid receptor RXR-γ promotes the development of neural precursor cells and remyelination (Huang JK et al. Nat Neurosci. 2011;14[1]:45-53). They found that when they blocked the action of RXR-γ in mice, neural precursor cells failed to fully develop in regions where demyelination had occurred. Additionally, they found that they could increase remyelination by adding an RXR-γ agonist to demyelinated neural cell cultures or administering it to rats that had undergone demyelination.

    Such research efforts aim to direct the brain's endogenous repair mechanisms to promote repair in MS and similar conditions.

    “We know the brain has stem cells that repair damage very effectively,” said Charles ffrench-Constant, MD, PhD, chair of medical neurology at the University of Edinburgh, United Kingdom, one of the National MS Society's team leaders and a member of the team that published the RXR-γ work. “We're trying to find ways to activate stem cells in the brain to kick-start the repair process.”

    Human safety studies of another agent that promotes remyelination are being conducted by Biogen Idec Inc in Cambridge, Mass, Coetzee noted. Previously, scientists working with the company have demonstrated that an antagonist of leucine-rich repeat and immunoglobulin-like domain–containing nogo receptor–interacting protein 1 (LINGO-1) promotes restoration of function and remyelination in an animal model of an MS-like condition (Mi S et al. Nat Med. 2007;13[10]:1228-1233).


    Calabresi and Gavin Giovannoni, MD, PhD, chair of neurology at Barts and The London School of Medicine and Dentistry in the United Kingdom, both team leaders in the National MS Society effort, noted that both of their laboratories are using high-throughput methods to identify other neuroprotective or remyelination agents. Calabresi said that some of the agents identified so far are drugs that are currently used and could rapidly enter clinical trials, while others will require further development before undergoing safety testing.

    But Giovannoni cautioned that it's important for patients and physicians to have realistic expectations about when such therapies might become available. He noted that it took about 15 years to get interferon beta from early clinical work to the clinic, and he added that if the LINGO-1 antagonist succeeds in clinical testing, he would be surprised if it became available in less than 10 years.

    Autologous stem cell transplants have been studied in a number of clinical trials as an immunosuppressive therapy for patients with MS, according to Gianvito Martino, MD, director of the division of neuroscience at San Raffaele Hospital in Milan. But scientists are also probing the potential of such stem cells as neural precursor cells to serve as neuroregenerative treatments in patients with MS.


    In May 2009, representatives from MS societies from the United States, United Kingdom, Italy, France, Canada, and Australia met with scientists from around the world to produce a consensus statement on the use of stem cell therapies in MS. A year later, the resulting statement and a review of the state of research in this area were published by Martino and colleagues involved in the consensus group (Martino G et al. Nat Rev Neurol. 2010;6[5]:247-255).

    The review stated that intravenous or intrathecal administration of neural stem or precursor cells and bone-derived mesenchymal stem cells has reliably produced therapeutic effects in rodents and primates with an MS-like disorder. Both types of stem cells have been found to have immunomodulatory effects. Additionally, mesenchymal stem cells have been found to secrete biological factors that inhibit scarring and cell death and promote angiogenesis and the creation of more endogenous precursor or stem cells. Transplanted neural precursor cells have been demonstrated to trigger remyelination of neurons in cells from both humans and animals and in animals with disorders that cause demyelination.

    Based on these findings, the consensus group arrived at several conclusions, including these:

    Preliminary clinical trials of mesenchymal and neural precursor cells to treat progressive MS should be considered.

    Trials of such prospective therapies should follow the guidelines of the International Society for Cellular Therapy and the International Society for Stem Cell Research.

    All such trials should be registered and data and methods shared.
    “We are at the point where we can start assessing the safety of these cells,” Martino said. “That is the main goal for the next 4 to 5 years.”

    In addition to developing scientific consensus on the state of the research in this area, the consensus group produced resources and recommendations to aid physicians and patients. The group created a brochure for patients summarizing their findings (, which is being distributed by MS societies around the world.


    The consensus group also agreed that patients should be discouraged from seeking care at stem cell clinics offering treatments that do not follow the group’s recommendations. Martino said that it may be risky for patients to receive care from some clinics around the world that are offering stem cell therapies for MS outside of clinical trials. He explained that growth of stem cells for transplant requires strict controls on cell growth and sterility to prevent cell lines from growing uncontrollably or becoming infected. He noted that some physicians in the field are seeing patients who have developed tumors and other adverse events after transplants at such clinics.

    Having such a strong consensus among MS societies and researchers from around the world is important, emphasized Martino. “If all agree, it is much better for the patient,” he said.

    Coetzee said that clinical trials of stem cell therapies to treat other types of neurologic disorders or damage may also help advance the understanding of the neuroregenerative potential of stem cells. For example, a phase 1 trial is under way to determine whether neural stem cells are a safe treatment for children with Pelizaeus-Merzbacher disease. The disorder is caused by a mutated gene on the X chromosome and affects only males. Boys who inherit the defective gene from their mothers are unable to produce myelin; without myelin, the children develop progressive language and motor problems. Those with the most severe form of the disease die in early childhood. If the trial is successful, ffrench-Constant said, “it would be an important proof of principle” with implications for MS.

    Coetzee cautioned that unlike MS, Pelizaeus-Merzbacher disease doesn't have an inflammatory component. “In MS, you always have to think about [inflammation],” he said. Even if restorative therapies prove successful in clinical trials, future therapies for MS will likely entail a combination of anti-inflammatory, restorative, and neuroprotective agents.

    “There are no silver bullets,” he said.

    Source: The Journal of American Medical Association © 2011 American Medical Association. (02/03/11)

    Beating the myelin regeneration blockers

    MyelinIt's known that the development of neuronal diseases such as multiple sclerosis and Alzheimer's disease is connected with the levels of myelin an insulating substance around nerve fibres in the body, although the actual causes of these conditions remain unknown.

    Now researchers at IBEC have discovered a new group of interacting partners for myelin-associated receptors, which could shed light on the significance of imbalanced production or modifications of the substance.

    In a study published online by the FASEB journal this week, group leader José Antonio del Río, together with his postdocs Vanessa Gil and Franc Llorens, have been looking at axons, ligands and receptors in the mammalian central nervous system. Following injury in adults, axons have a limited capacity for regrowth; this restriction is caused by myelin-associated inhibitors (MAIs).

    A release from myelin inhibition thus improves neuronal regeneration, and the three researchers from IBEC's Molecular and Cellular Neurobiotechnology group have discovered that blocking two of some of these proteins' shared receptors NgR1, together with its coreceptors p75(NTR), TROY and Lingo-1, and paired immunoglobulin-like receptor B (PirB) prevents the inhibitors from restricting axonal sprouting and limiting the regeneration of damaged fibre tracts.

    Other elements of the myelin inhibitory pathway are still unknown, but this identification and characterization of the roles and functions of some of the inhibitory molecules sheds light on one of the most competitive areas of research into neuroregeneration of the past several years. In addition, further data from within and outside the CNS environment suggests that most of these proteins have other roles beyond axonal growth inhibition.

    "Potentially there could be new physiological roles for them in other processes such as development, neuronal homeostasis, plasticity and neurodegeneration," says José Antonio. "Modifications could be considered as markers for certain neuronal diseases."

    Source: Medical News Today © 2010 MediLexicon International Ltd (14/11/10)

    Oestrogen receptor {beta} ligand: a novel treatment to enhance endogenous functional remyelination

    Demyelinating diseases, such as multiple sclerosis, are characterized by inflammatory demyelination and neurodegeneration of the central nervous system. Therapeutic strategies that induce effective neuroprotection and enhance intrinsic repair mechanisms are central goals for future therapy of multiple sclerosis.

    Oestrogens and oestrogen receptor ligands are promising treatments to prevent multiple sclerosis-induced neurodegeneration.

    In the present study we investigated the capacity of oestrogen receptor β ligand treatment to affect callosal axon demyelination and stimulate endogenous myelination in chronic experimental autoimmune encephalomyelitis using electrophysiology, electron microscopy, immunohistochemistry and tract-tracing methods.

    Oestrogen receptor β ligand treatment of experimental autoimmune encephalomyelitis mice prevented both histopathological and functional abnormalities of callosal axons despite the presence of inflammation.

    Specifically, there were fewer demyelinated, damaged axons and more myelinated axons with intact nodes of Ranvier in oestrogen receptor β ligand-treated mice.

    In addition, oestrogen receptor β ligand treatment caused an increase in mature oligodendrocyte numbers, a significant increase in myelin sheath thickness and axon transport.

    Functional analysis of callosal axon conduction showed a significant improvement in compound action potential amplitudes, latency and in axon refractoriness.

    These findings show a direct neuroprotective effect of oestrogen receptor β ligand treatment on oligodendrocyte differentiation, myelination and axon conduction during experimental autoimmune encephalomyelitis.

    Crawford DK, Mangiardi M, Song B, Patel R, Du S, Sofroniew MV, Voskuhl RR, Tiwari-Woodruff SK.

    1 Multiple Sclerosis Programme, Department of Neurology, School of Medicine, University of California, Los Angeles, CA 90095, USA.

    Source: Brain. 2010 Sep 21 & Pubmed PMID: 20858739 (29/09/10)

    Demyelination versus remyelination in progressive MS
    The causes of incomplete remyelination in progressive multiple sclerosis are unknown, as are the pathological correlates of the different clinical characteristics of patients with primary and secondary progressive disease.

    We analysed brains and spinal cords from 51 patients with progressive multiple sclerosis by planimetry.

    Thirteen patients with primary progressive disease were compared with 34 with secondary progressive disease.

    In patients with secondary progressive multiple sclerosis, we found larger brain plaques, more demyelination in total and higher brain loads of active demyelination compared with patients with primary progressive disease. In addition, the brain density of plaques with high-grade inflammation and active demyelination was highest in secondary progressive multiple sclerosis and remained ∼18% higher than in primary progressive multiple sclerosis after adjustments for other plaque types and plaque number (P < 0.05).

    Conversely, the proportion of remyelinated shadow plaques (P < 0.05) and the overall remyelination capacity (P < 0.01) per brain were higher in primary, compared with secondary, progressive multiple sclerosis.

    By contrast, there were no group differences in the brain load or frequency of low-grade inflammatory plaques with slowly expanding demyelination.

    Spinal cord lesion loads and remyelination capacity were also comparable in the two patient groups. Remyelinated areas were more vulnerable than the normal-appearing white matter to new demyelination, including active demyelination in secondary progressive multiple sclerosis.

    'Recurrent' slowly expanding demyelination, affecting remyelinated areas, and the load of slowly expanding demyelination correlated with incomplete remyelination in both groups. In turn, incomplete remyelination in the spinal cord correlated with higher disease-related disability (determined retrospectively; r = -0.53; P < 0.05 for remyelination capacity versus disease severity). By contrast, such a correlation was not observed in the brain.

    We propose that regulatory and reparative properties could protect the white matter of the brain in patients with primary progressive multiple sclerosis. These patients may, thereby, be spared symptoms until the spinal cord is affected. By contrast, recurrent active demyelination of repaired myelin could explain why similar symptoms often develop in consecutive relapses in relapsing-remitting/secondary progressive multiple sclerosis.

    Our data also indicate that slowly expanding demyelination may irreparably destroy normal and repaired myelin, supporting the concept of slowly expanding demyelination as an important pathological correlate of clinical progression.

    Bramow S, Frischer JM, Lassmann H, Koch-Henriksen N, Lucchinetti CF, Sørensen PS, Laursen H.

    1 Laboratory of Neuropathology, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.

    Source: Brain. 2010 Sep 20. & Pubmed PMID: 20855416 (29/09/10)

    Protein lets brain repair damage from multiple sclerosis, other disorders

    MyelinA protein that helps build the brain in infants and children may aid efforts to restore damage from multiple sclerosis (MS) and other neurodegenerative diseases, researchers at Washington University School of Medicine in St. Louis have found.

    In a mouse model of MS, researchers found that the protein, CXCR4, is essential for repairing myelin, a protective sheath that covers nerve cell branches. MS and other disorders damage myelin, and this damage is linked to loss of the branches inside the myelin.

    "In MS patients, myelin repair occurs inconsistently for reasons that aren't clear," says senior author Robyn Klein, MD, PhD, associate professor of medicine and of neurobiology. "Understanding the nature of that problem is a priority because when myelin isn't repaired, the chances that an MS flare-up will inflict lasting harm seem to increase."

    The findings appear online in The Proceedings of the National Academy of Sciences.

    Mouse models typically mimic MS symptoms by causing chronic immune cell infiltration in the brain, but, according to Klein, the ongoing immune damage caused by the cells makes it difficult for researchers to focus on what the brain does to repair myelin.

    For the study, Klein and first author and postdoctoral fellow Jigisha Patel, PhD, used a non-inflammatory model that involves giving mice food containing cuprizone, a compound that causes the death of cells that form myelin in the central nervous system. After six weeks, these cells, known as oligodendrocytes, are dead, and the corpus callosum, a structure that connects the left and right hemispheres of the brain, has lost its myelin. If cuprizone is then removed from the mouse diet, new cells migrate to the area that restore the myelin by becoming mature oligodendrocytes.

    Klein's investigations began with the processes triggered by dying oligodendrocytes while mice are still on the cuprizone diet. The dying cells activate other support cells in the brain, causing them to express inflammatory factors.

    Klein showed that levels of a receptor for inflammatory factors, CXCR4, peaked at six weeks. If researchers continued feeding the mice cuprizone for 12 weeks, levels of the inflammatory factor and its receptor dropped significantly. At 12 weeks the mice were also unable to restore myelin, suggesting a potential connection between myelin repair and CXCR4.

    "This was a surprise, because the main thing CXCR4 has been known for is its role in forming the brain, not healing the brain," Klein says. "But we did know that injury increases the number of brain cells that make CXCR4, so it wasn't an unreasonable place to look."

    Klein showed that the cells destined to become oligodendrocytes and repair myelin damage, known as neural precursor cells, have high levels of the CXCR4. The cells come up to the corpus callosum from an area below the ventricles, a noncellular area filled with cerebrospinal fluid.

    When scientists blocked CXCR4 from becoming activated or reduced cells' ability to make it, the mice were unable to restore myelin. Neural precursor cells stayed in the ventricle and grew in number but did not move to the corpus callosum to begin repairs.

    "Apparently the neural precursor cells have to stop proliferating before they can migrate, and CXCR4 plays a role in this change," Klein says. "CXCR4 also seems to be essential to the cells' ability to develop into mature oligodendrocytes and form myelin."

    Klein plans to see if she can restore myelin repair in genetically engineered mouse models of MS with a genetically altered lentivirus that increases levels of an inflammatory factor that activates CXCR4. She also will work with Washington University colleagues to study the new model with advanced imaging techniques in an attempt to further clarify the relationship between loss of nerve cell branches and myelin damage in MS.

    "We do not yet know if this myelin repair pathway is somehow damaged or impaired in MS patients," Klein says. "But I like the idea of turning on something that the brain already knows how to make by itself, allowing it to heal itself with its own molecules."

    Patel JR, McCandless EE, Dorsey D, Klein RS. CXCR4 promotes differentiation of oligodendrocytes progenitors and remyelination. Proceedings of the National Academy of Sciences, published online May 31, 2010.

    Funding from the National Institutes of Health and the National Institute of Neurological Disorders and Stroke supported this research.

    Source: Eureka Alert! (08/06/10)

    Researchers explore new ways to reverse MS damage

    MyelinA National Institutes of Health grant will help University of Central Florida researchers explore new ways to potentially reverse the damage caused by multiple sclerosis and other neurological disorders. 

    Stephen Lambert, an associate professor in the College of Medicine and a member of UCF's Hybrid Systems Laboratory, has received $428,000, the first installment of a four-year, $1.9 million project. His team will study the breakdown of myelin, a substance that coats and protects nerves inside the brain and spinal cord, enabling electrical signals to reach distant nerve cells and muscles. 

    About 400,000 Americans and about 2.5 million people worldwide suffer from MS, according to the National Multiple Sclerosis Society. The drugs that are available now focus mainly on controlling the inflammatory nature of the diseases to limit the development of neuronal damage. They do not reverse the damage caused by the diseases. 

    "The process of myelination is extremely complex. By reproducing these complex phenomena in our laboratories, we can learn more about what causes debilitating diseases that affect so many people around the world," Lambert said. "We hope our research will ultimately lead to new drugs that reverse the damage caused by these diseases and help patients lead longer, healthier lives."

    Most of the research will take place in the Hybrid Systems Lab in UCF's NanoScience Technology Center. At the center, a research team led by UCF bioengineer James Hickman showed for the first time last year that specialized myelin coating could be produced in the lab environment without the use of any type of growth serum.

    The finding is significant because it allows researchers to more clearly study the causes of breaks in myelin and also the impact of proposed chemical treatments. Both could potentially lead to a greater understanding of the causes of neurological disorders such as MS and diabetes-induced peripheral neuropathy.

    Hickman's previous work focused on cells in the peripheral nervous system and the nerves that connect the body's limbs and organs to the brain. The new research will, for the first time, explore the breakdown of myelin in the areas inside the brain and the spinal cord using nanotechnology tools.

    "The application of the high-tech tools developed in my lab at the NanoScience Center to this complex problem brings us that much closer to developing new drugs and, at some stage, a cure for diseases such as MS," Hickman said. 

    Source: Nanowerk ©2010, Nanowerk (11/05/10)

    Early protein processes crucial to formation and layering of myelin membrane

    Myelin and MSNew findings from an international team of researchers probing the nerve-insulating myelin sheath were bolstered by the work of Boston College biologists, who used x-rays to uncover how mutations affect the structure of myelin, a focal point of research in multiple sclerosis and other neurological disorders.

    The findings were central to the group's broader conclusion that a set of protein processes required in the early-stage conversion of glucose into fatty acids are critical to the proper formation and layering of myelin membrane, the researchers report in the Proceedings of the National Academy of Sciences.

    Boston College Professor of Biology Daniel Kirschner, Senior Research Associate Hideyo Inouye, graduate student Adrienne Luoma, and undergraduate Michelle Crowther partnered with Dutch, Italian, Swiss and Japanese scientists. The research group looked at the composition of myelin lipids for clues about their role in myelin structure and stability, Kirschner said. Myelin sheaths surround the axons of neurons and are considered critical to the proper functioning of the nervous system.

    "Myelin is a stack of membranes providing insulation to the axon and with that insulation comes rapid nerve conduction," said Kirschner. "If myelin becomes defective, the membranous insulator becomes leaky and the nerve doesn't conduct as well. If myelin is totally missing along part of an axon, the nerve conduction is blocked."

    Using x-ray diffraction, Kirschner's group captured a view of the dynamic membrane assembly in whole nerve samples taken from mice engineered to mimic myelinic diseases. Compared to other microscopy techniques used in the study of myelinated tissue, x-ray diffraction delivers clearer, cleaner and quicker results about the structural integrity of internodal myelin, Kirschner said.

    "We were able to tell that the packing of the membranes was abnormal, which could affect the electrophysical properties of myelin," said Kirschner. "We also saw that the packing of the lipids in the myelin lipid bilayers was more disordered in samples from the transgenic mice used here."

    Other types of microscopy introduce chemical modifications to the tissue under study. These agents and the time involved in preparing and analyzing such samples can alter the molecular structure and mask the dynamic interactions of myelin. X-ray diffraction requires no chemical treatments and can be completed in about an hour, Kirschner said.

    "The advantages of x-ray diffraction are that we can examine and analyze whole pieces of tissue and give information about the effect of the mutation on the native structure of the myelin as well as on its stability," said Kirschner.

    The researchers have been focusing on genetically modified mice for approximately four years as part of research into the role of myelin degeneration in a range of diseases of the central and peripheral nervous systems. Kirschner says his team is also exploring use of the technique in animal models of spinal cord injury and repair.

    Source: Medical News Today © 2009 MediLexicon International Ltd (27/11/09)

    Multiple Sclerosis study offers theory for why repair of brain's wiring fails

    MS MRI

    Scientists have uncovered new evidence suggesting that damage to nerve cells in people with multiple sclerosis accumulates because the body's natural mechanism for repair of the nerve coating called "myelin" stalls out.

    The study, published today, July 1, 2009, in the print edition of "Genes & Development," was conducted by scientists at the University of California, San Francisco and University of Cambridge. The research was led by co-senior investigator David Rowitch, MD, PhD, a Howard Hughes Medical Institute investigator at UCSF.

    The investigation, conducted in mice and in human tissue, showed that repair of nerve fibers is hampered by biochemical signals that inhibit the development of cells known as oligodendrocytes, which function as repair workers in the brain.

    Oligodendrocytes form a protective sheath, known as myelin, that insulates the fibrous cables, or axons, radiating from nerve cells. In multiple sclerosis, the immune system's T cells and B cells attack oligodendrocytes, ultimately damaging the myelin sheath to the point that the electrical signals transmitted by the axons beneath it are disrupted.

    Remarkably, the brain generally is able to recruit fresh, immature oligodendrocytes to the myelin sheath to repair the damage, for a time. This explains why, in the most common form of the disease, known as relapsing remitting MS, the symptoms -- which range from tingling and numbness in the limbs to loss of vision and paralysis -- disappear or are greatly reduced, for some times months or years at a time.

    Ultimately, however, the repair process falters and the disease progresses. In their study, the team set out to see if they could determine what was slowing down myelin repair. They lesioned a small region of white matter in healthy mice, then monitored the repair process, examining the tissue after five, 10, and 14 days.

    To find out which genes were contributing to three key stages in the repair process – the recruitment of oligodendrocyte precursors to the site of injury, the maturation of those cells into functional oligodendrocytes, and the formation of a new myelin sheath -- they measured the activity of 1,040 genes. All of the genes they studied encode transcription factors, which regulate the activity of other genes. Their experiments showed that 50 transcription factors are working during key steps in myelin repair.

    The team then honed in on a gene called Tcf4, because its expression was strong in damaged areas where repair attempts were under way.

    Tcf4 is involved in a cascade of biochemical events known as the Wnt (pronounced "wint") pathway, whose importance has been well recognized in normal development of many tissues, including the brain. Until now, however, Wnt had not been linked to myelin production or repair.

    "This is the first evidence implicating the Wnt pathway in multiple sclerosis," says lead author Stephen P.J. Fancy, PhD, a postdoctoral fellow in the Rowitch lab. "We consider this an exciting development in our efforts to understand why the repair process often fails in the disease."

    To glean further evidence about Wnt's role, the researchers hyperactivated the Wnt pathway in the oligodendrocytes of mice, which caused a profound delay in repair. Further analysis suggested that the Wnt pathway activation was creating a roadblock that prolonged oligodendrocyte precursor development.

    "While the animals eventually showed repair, it was delayed compared to normal mice," says Fancy. The researchers also tested human tissue for the presence of Tcf4, and found the protein in areas damaged by MS but not in healthy white matter. Further, the researchers examined available data from another study and found that many signaling molecules of the Wnt pathway are overactive in lesions of patients with MS.

    "This is an important step that we hope will lead to targeted therapies involving the repair process," says co-senior author Robin Franklin of the University of Cambridge.

    Now the team is starting to examine some of the other genes it found to be active in the myelin repair process, and is developing new mouse models to help test potential therapies that might manipulate the Wnt pathway to improve myelin repair. Given the pathway's role in so many different processes, however, Rowitch cautioned that targeting Wnt could cause unintended side effects.

    The new work may also have implications for another neurological disease, periventricular leukomalacia, which can lead to cerebral palsy in extremely premature infants, says Rowitch. Recent studies by Rowitch and colleagues show a similar inability of oligodendrocytes to perform their important repair function.

    "The researchers have made an encouraging finding that could open a new window into the cause of failed neural repair in multiple sclerosis," says Dr. Patricia O'Looney, Vice President of BioMedical Research at the National Multiple Sclerosis Society. "Understanding such mechanisms should help advance the efforts to find valuable treatments for this debilitating disease."

    Source: Eureka Alert! (01/07/09)

    Protein identified as critical to insulating the body's wiring could also become treatment target in Multiple Sclerosis

    Myelin in MS

    A new protein identified as critical to insulating the wiring that connects the brain and body could one day be a treatment target for divergent diseases, from rare ones that lower the pain threshold to cancer, Medical College of Georgia researchers say.

    They report this week in Proceedings of the National Academy of Sciences Online Early Edition that in the peripheral nervous system that controls arms and legs, the protein erbin regulates the protein neuregulin 1, stabilizing and interacting with the ErbB2 receptor on Schwann cells so they can make myelin, which insulates the wiring.

    Their studies in mice have shown that when erbin is missing or mutated, the insulation is inadequate, slowing communication.

    "Erbin is like a tuner to make signaling stronger or weaker," says Dr. Lin Mei, the study's corresponding author and director of MCG's Institute of Molecular Medicine and Genetics.

    Without erbin, the myelin production system falls apart. Eventually raw, over-exposed nerves can die.

    "Receptors for neuregulin 1 just get degraded and lost," says Dr. Mei, Georgia Research Alliance Eminent Scholar in Neuroscience. "Schwann cells can see neuregulin 1 sitting there but they can't do anything without the receptor."

    Impaired myelin formation and maintenance is implicated in a variety of neurological and psychiatric diseases including schizophrenia, multiple sclerosis and Charcot-Marie-Tooth neuropathy, a genetic, progressive disease that weakens muscles.

    Cancer is an issue because the ErbB2 receptor also is an oncogene highly expressed in tumors. ErbB2 helps cancer cells grow and spread so finding its role in the receptor's stability and function provides a potential new site for targeted cancer therapy, says Dr. Yanmei Tao says, postdoctoral fellow in neurobiology and the study's first author. In fact, antibodies to ErbB2 already are available to patients with breast and prostate.

    Source: Bio-Medicine © 2003-2009 Bio-Medicine. (20/05/09)

    Researchers identify pathway to reactivate myelin repair

    Myelin Damage In MS

    UMDNJ researchers have identified a key pathway that could lead to new therapies to repair nerve cells’ protective coating stripped away as a result of autoimmune diseases such as Multiple Sclerosis (MS). An article reporting their findings will appear in the May 13 online edition of the Journal of Neuroscience.

    Myelin is fatty material that coats and protects the ends of nerve cells. The loss of myelin and myelin-producing cells impairs the ability of nerves to conduct signals. A severe loss may lead to erosion of nerve tissues and result in permanent damage.

    “In people with MS that is relapsing-remitting, the body can replace myelin that has been stripped away,” explained Teresa L. Wood, Ph.D., the study’s lead investigator. “But, after repeated attacks, that process of replacement no longer functions well,” she added.

    “Our data demonstrate that a novel cellular pathway, called the mammalian target of rapamycin (mTOR), regulates the generation of new myelin-producing cells (oligodendrocytes) and the production of myelin in immature rodent cells,” Wood said. She is a professor in the Department of Neurology & Neurosciences and the Rena Warshow Chair in Multiple Sclerosis at the UMDNJ-New Jersey Medical School.

    More work is needed to determine if the key to reactivate remyelination is to stimulate the pathway or if environmental impediments, such as inflammation, also must be overcome to allow the pathway to function normally. “Now at least we know a target to go after to promote repair,” she said.

    The researchers’ work may also lead to new therapies for other disorders where the myelin-producing cells are affected, such as autism, Alzheimer's disease, and perinatal brain injury.

    The University of Medicine and Dentistry of New Jersey (UMDNJ) is the nation’s largest free-standing public health sciences university with nearly 5,700 students attending the state's three medical schools, its only dental school, a graduate school of biomedical sciences, a school of health related professions, a school of nursing and its only school of public health on five campuses. Annually, there are more than two million patient visits at UMDNJ facilities and faculty practices at campuses in Newark, New Brunswick/Piscataway, Scotch Plains, Camden and Stratford. UMDNJ operates University Hospital, a Level I Trauma Center in Newark, and University Behavioral HealthCare, a statewide mental health and addiction services network.

    Source: Medical Technology (13/05/09)

    Cats' central nervous system can repair itself and restore function

    Scientists studying a mysterious neurological affliction in cats have discovered a surprising ability of the central nervous system to repair itself and restore function.

    In a study published March 30, 2009 in the Proceedings of the National Academy of Sciences, a team of researchers from the University of Wisconsin-Madison reports that the restoration in cats of myelin — a fatty insulator of nerve fibers that degrades in a host of human central nervous system disorders, the most common of which is multiple sclerosis — can lead to functional recovery.

    "The fundamental point of the study is that it proves unequivocally that extensive remyelination can lead to recovery from a severe neurological disorder," says Ian Duncan, the UW-Madison neuroscientist who led the research. "It indicates the profound ability of the central nervous system to repair itself."

    The finding is important because it underscores the validity of strategies to reestablish myelin as a therapy for treating a range of severe neurological diseases associated with the loss or damage of myelin, but where the nerves themselves remain intact.

    Myelin is a fatty substance that forms a sheath for nerve fibers, known as axons, and facilitates the conduction of nerve signals. Its loss through disease causes impairment of sensation, movement, cognition and other functions, depending on which nerves are affected.

    The new study arose from a mysterious affliction of pregnant cats. A company testing the effects on growth and development in cats using diets that had been irradiated reported that some cats developed severe neurological dysfunction, including movement disorders, vision loss and paralysis. Taken off the diet, the cats recovered slowly, but eventually all lost functions were restored.

    "After being on the diet for three to four months, the pregnant cats started to develop progressive neurological disease," says Duncan, a professor of medical sciences at the UW-Madison School of Veterinary Medicine and an authority on demyelinating diseases. "Cats put back on a normal diet recovered. It's a very puzzling demyelinating disease."

    The afflicted cats were shown to have severe and widely distributed demyelination of the central nervous system, according to Duncan. And while the neurological symptoms exhibited by the cats are similar to those experienced by humans with demyelination disorders, the malady does not seem to be like any of the known myelin-related diseases of humans.

    In cats removed from the diet, recovery was slow, but all of the previously demyelinated axons became remyelinated. The restored myelin sheaths, however, were not as thick as healthy myelin, Duncan notes.

    "It's not normal, but from a physiological standpoint, the thin myelin membrane restores function," he says. "It's doing what it is supposed to do."

    Knowing that the central nervous system retains the ability to forge new myelin sheaths anywhere the nerves themselves are preserved provides strong support for the idea that if myelin can be restored in diseases such as multiple sclerosis, it may be possible for patients to regain lost or impaired functions: "The key thing is that it absolutely confirms the notion that remyelinating strategies are clinically important," Duncan says.

    The exact cause of the neurological affliction in the cats on the experimental diet is unknown, says Duncan, who was not involved in the original study of diet.

    "We think it is extremely unlikely that [irradiated food] could become a human health problem," Duncan explains. "We think it is species specific. It's important to note these cats were fed a diet of irradiated food for a period of time."

    In addition to Duncan, authors of the new PNAS study include Alexandra Brower of the Wisconsin Veterinary Diagnostic Laboratory; Yoichi Kondo and Ronald Schultz of the UW-Madison School of Veterinary Medicine; and Joseph Curlee, Jr. of Harlan Laboratories in Madison.

    Source: Science Daily © 1995-2009 Science Daily LLC (01/04/09)

    Researchers disprove 15-year-old theory about the nervous system


    A delay in traffic may cause a headache, but a delay in the nervous system can cause much more. University of Missouri researchers have uncovered clues identifying which proteins are involved in the development of the nervous system and found that the proteins previously thought to play a significant role, in fact, do not. Understanding how the nervous system develops will give researchers a better understanding of neurological diseases, such as multiple sclerosis and Charcot-Marie-Tooth disorders.

    "Speed is the key to the nervous system," said Michael Garcia, investigator in the Christopher S. Bond Life Sciences Center and assistant professor of biological sciences in the MU College of Arts and Science. "The peripheral nervous system 'talks' to muscles through nerve impulses in response to external stimuli. When babies are born, they do not have fully developed nervous systems, and their systems run slower. Eventually, the nervous system matures. Our study tried to understand that maturation process."

    The process of nerve cells maturation is called myelination. During myelination, a layer of myelin (electrically insulating material) wraps or forms around the axons (part of the nerve cell that conducts electrical impulses). Nerve impulses travel faster in myelinated nerve cells.

    "Myelination is important for signal transmission because it increases nerve conduction velocity," Garcia said. "The relationship between axons and myelinating cells is a reciprocal one, with each cell type sending and receiving signals from the other cell. One signal originates from myelinating cells and results in a large increase in axonal diameter."

    When nerve cells are unmyelinated, the axon has a smaller diameter and contains neurofilaments that are less modified and are more compact. Neurofilaments are a group of proteins that are essential for diameter growth. The protein group includes neurofilament subunits that are classified as light, medium and heavy. Loss of all neurofilaments in the axon results in myelinated axons with slowed conduction velocities.

    For the last 15 years, the proposed underlying mechanism for an axon's diameter growth has focused on myelin-dependent modification of regions of neurofilaments that are located within the heavy and medium subunits. In a previous study, genetically removing the region of the medium subunit that is modified impaired growth and slowed nerve conduction. However, this did not directly test if the proposed modification was required as a much larger region was genetically removed.

    In the current study, researchers genetically altered the neurofilament medium subunit such that it could no longer be modified in response to myelination. Surprisingly, Garcia found that prevention of what was thought to be an extremely important modification did not affect axonal diameter.

    "It is now clear that the basic mechanism for how neurofilaments affect axonal diameters remains unanswered," Garcia said. "This discovery introduces a lot of new questions."

    Source: e! Science News © 2009 Eureka! Science News (04/02/09)

    Turning down gene expression promotes nerve cell maintenance

    Anyone with a sweet tooth knows that too much of a good thing can lead to negative consequences. The same can be said about the signals that help maintain nerve cells, as demonstrated in a new study of myelin, a protein key to efficient neuronal transmission.

    Normal nerve cells have a myelin sheath, which, much like the insulation on a cable, allows for rapid and efficient signal conduction. However, in several diseases the most well-known being multiple sclerosis demyelination processes cause the breakdown of this "insulation", and lead to deficits in perception, movement, cognition, etc. Thus, in order to help patients of demyelinating disease, researchers are studying the pathways that control myelin formation and maintenance.

    A new study by University of California scientists examines the role of a structural protein, called lamin, in maintaining myelin. They found that, while lamin is necessary in the initial stages of myelin formation, too much lamin promotes myelin breakdown. Further investigation led the researchers to the discovery of a signal that fine-tunes lamin expression. This signal, a microRNA called miR-23, can turn down lamin gene expression, and thereby prevent demyelination due to lamin overexpression.

    This new work reported in Disease Models & Mechanisms (DMM),, adds another piece to the puzzle that is understanding myelin formation and maintenance. Additionally, the identification of miR-23 as a myelin regulator introduces a new potential drug target in developing treatments for demyelinating illness.

    Source: Bio-Medicine © 2003-2008 Bio-Medicine. (02/02/09)

    New Biogen drug seeks to repair Multiple Sclerosis damage

    Myelin damage in MS

    Reversing the damage done by multiple sclerosis would be a dream come true for patients of the debilitating disease, and there is some promising research working toward that goal.

    The condition is thought to occur when the body literally attacks itself and current therapies only seek to slow or stop that situation. But Biogen Idec Inc. (BIIB) is developing a drug that may repair the damage to the nervous system from the disease, a prospect that could also aid victims of other neurological conditions.

    "This is the first entry into our clinical pipeline, or really in anyone else's pipeline that we are aware of, for a truly restorative therapy for MS," said Ken Rhodes, vice president of discovery neurobiology at Biogen.

    Though the Cambridge, Mass., biotech company is hopeful for the drug's development, it is yet to be tested in humans and, assuming success, it wouldn't be available to patients for many years.

    Much remains unknown about multiple sclerosis, but it is thought to be an autoimmune disease that occurs when the body attacks myelin, the protective insulation surrounding the nerve fibers called axons in the central nervous system. The myelin damage can distort or block messages carried by the axons and result in a wide variety of symptoms such as vision problems, limb numbness and paralysis.

    Though the cause is a mystery, MS is thought to develop from some degree of genetic predisposition working in combination with environmental triggers earlier in the life. It is more common in women and tends to develop between the ages of 20 and 50, according to the National Multiple Sclerosis Society.

    Current treatments for the disease all involve trying to alter the immune system's ability to attack the nervous systems, notes John Richert, executive vice president of research and clinical programs for the MS Society.

    A popular group of drugs are the beta-interferons, which reduce disease flare ups and are similar to proteins that play a role in the immune system. Those are Biogen's Avonex, Bayer AG's (BAY.XE) Betaseron, and Rebif, marketed by Pfizer Inc. (PFE) and Germany's Merck KGaA (MRK.XE).

    Teva Pharmaceuticals Industries Inc. (TEVA) makes Copaxone, which seems to fight the nerve-attacking immune cells by acting as a myelin decoy. Biogen and partner Elan Plc (ELN) also sell Tysabri, which prevents those immune cells leaving the blood stream so that they can't get to the brain or spinal cord.

    Early Success

    The focus of much of Biogen's current discovery research in MS is focused on restorative therapy, but its most advanced program is led by biologist Sha Mi, who joined the company in 2000 and studied why the axons in MS lesions weren't generating new myelin.

    Research found that cells called oligodendrocytes were being prevented from undergoing the needed differentiation for them to build new myelin.

    Furthermore, Mi found that the so-called LINGO molecule was inhibiting that differentiation and that using an antibody to block LINGO's function could allow myelin to regenerate.

    "When we block LINGO function, we can see robust oligodendrocyte differentiation, and they interact with the axon for remylination," said Mi.

    The antibody has been shown to be effective in mouse models that are accepted as being useful for mimicking the properties of MS.

    The antibody helped the mice grow new myelin, and it also helped with the integrity of the nerve fibers, in comparison to untreated mice, thus aiding nerve function. More myelin growth occurred closer to the site of the antibody application, also suggesting its responsibility for the effects.

    The research showed that the antibody didn't prevent the loss of myelin in an animal model, but it did reduce the effects of disease progression.

    Though the development is clearly exciting, the antibody is only in toxicity studies that are expected to be completed later this year. Biogen expects to file an Investigational New Drug application with Food and Drug Administration in the fourth quarter and begin human studies starting shortly thereafter.

    Rhodes noted that the next goal is to conduct proof-of-concept studies to determine if the drug inhibits LINGO function in humans with the same positive effects.

    Hopeful Future

    The possibility of repairing damage done by MS and reducing symptoms of the disease would be revolutionary for MS patients, but Dr. Richert believes that currently used therapies are likely to continue as the best treatment for new patients who may not have a lot of nerve damage.

    Regeneration would be used on patients who already have neurological deficits, he said, as well as those whose disease continues to progress regardless of treatment.

    In order to provide the best benefit, Dr. Rhodes said that the anti-LINGO antibody would likely be used in combination with one of the more traditional immunosupressive approaches.

    "As you dampen the immune response, you treat with anti-LINGO to try and actually facilitate recovery and repair," he said.

    If successful, the antibody could have a future in treating other neurological disease such as Parkinson's, or even help repair damage done to the spinal cord.

    Biogen has a number of programs to explore the antibody's use in other diseases but is cautious on any of those prospects.

    "The preclinical data supporting the utility of those indications isn't as well developed yet as it is with MS," Dr. Rhodes said.

    Source: CNN © 2009 Inc. (14/01/09)

    Netrin-1 possible key to Multiple Sclerosis demyelination

    Myelin and MS

    Scientists find key step in maintaining myelin.

    In a new study, researchers at the Montreal Neurological Institute (MNI), McGill University, and the Université de Montréal have discovered an essential mechanism for the maintenance of the normal structure of myelin, the protective covering that insulates and supports nerve cells (neurons). Up until now, very little was known about myelin maintenance.

    This new information provides vital insight into diseases such as Multiple Sclerosis (MS) and other progressive demyelinating diseases in which myelin is destroyed, causing irreversible damage and disrupting the nerve cells' ability to transmit messages. The research, published recently in the Journal of Neuroscience, is the first to identify a role for the protein netrin-1, previously characterised only in the developing nervous system, with this critical function in the adult nervous system. This research was funded by the MS Society of Canada and the Canadian Institutes of Health Research.

    Netrin-1, a protein deriving its name from the ancient Indian language, Sanskrit, word for 'one who guides,' is known to guide and direct nerve cell axons to their targets. In the molecular biological studies conducted by the team, they found that blocking the function of netrin-1 and one of its receptors in adult neural tissue causes the disruption of myelin.

    "We've known for just over 10 years that netrin is essential for normal development of the nervous system, and we also knew that netrin was present in the adult brain, but we didn't know why. It is fascinating that netrin-1 has such a vital role in maintaining the structure of myelin in the adult nervous system," says Dr. Tim Kennedy, a neuroscientist at the MNI and the senior investigator of this study, "continuing to pursue the implications of that are incredibly exciting."

    "Our mission is to find a cure as quickly as possible and enhance quality of life," says Karen Lee, assistant vice-president of research programs for the MS Society of Canada. "We are pleased to be involved in funding work that supports our mission and feel that this research takes us closer to understanding the players and processes that could aid in remyelination."

    The results of this study, a collaboration between Dr. Kennedy's laboratory, clinician-scientists in the Neuroimmunology group at the MNI headed by Dr. Jack Antel, and Dr. Adriana Di Polo's laboratory at the Université de Montréal, are especially significant in Canada which has one of the highest rates of Multiple Sclerosis (MS) in the world with approximately 1,000 new cases of MS diagnosed each year.

    ''This is an exciting new area of research that could lead to new treatment strategies and ultimately improve the life of the people who suffer from MS. We are proud to be funding this collaborative research between basic and clinician-scientists," said Dr. Rémi Quirion, Scientific Director of the CIHR Institute of Neurosciences, Mental Health and Addiction.

    MS is a disease of the central nervous system in which myelin is destroyed. Understanding the factors involved in maintaining myelin and promoting remyelination, offers new therapeutic targets and avenues for the treatment of MS. As described by Dr. Jack Antel, "Current MS therapies aim to block inflammation. In order to protect and restore myelin it is essential to to understand the molecules involved in these processes. This is the new era of the neurobiology of MS." The team is taking the investigation further by teaming up with the MS clinic and doctors at the MNI, providing access to a huge amount of patient data, and enabling them a broader clinical perspective.

    Importantly, this newly discovered mechanism implicates a cascade of protein molecules that have not been known to be involved in myelination. The study was carried out in mice and using in vitro cell cultures. The investigators found that myelin develops normally, but then begins to come apart. Interestingly, in some respects this mirrors what happens in some demyelinating diseases like MS, where myelin forms and may be stable for years, but is then disrupted and begins to fail. Specifically, the new findings show that netrin-1 and its receptor are needed to hold paranodal junctions in place, and thereby maintain the structure of myelin.

    The paranodal junction is a highly specialized region of contact where an oligodendrocyte cell attaches itself to the nerve cell's axon. This juncture acts as a molecular fence, which organizes and segregates the distribution of key proteins along the nerve cells axon and plays an imperative role in the proper conduction of electrical signals along the length of the nerve cell. When the function of netrin-1 and its receptor is disrupted, the organization of this adhesive junction comes apart, disrupting the function of nerve cells in the brain and spinal cord.

    Source: Eureka Alert! (13/11/08)

    Multiple sclerosis research may speed up with new mouse model of disease


    A new study highlights the role of a charge-switching enzyme in nervous system deficits characteristic of multiple sclerosis and other related neurological illness.

    Multiple sclerosis (MS) is one of several diseases in which myelin – the insulator for electrical signaling in the nervous system – breaks down and causes severe deficits in brain and nerve function. Much like the rubber insulation on an electrical cord, myelin surrounds long projections from the body of a neuron, and allows signals to travel down the cell with speed and efficiency. Patients with MS and other "de-myelinating" diseases therefore suffer deficits in balance, coordination, and movement, as well as sensory disturbances, from the loss of this neuronal insulation.

    A major research initiative in treating these diseases is identifying the molecular factors and changes that lead to myelin breakdown.

    In a new study published in Disease Models & Mechanisms a team of Canadian researchers report on a new mouse model of disease which will help in understanding how demyelination occurs.

    Previous research had identified that an enzyme known as peptidylarginine deiminase 2, or PAD2, is increased in patients with MS, and that PAD2 switches a charge on a protein key to myelin stability. Therefore, Abdiwahab A. Musse and colleagues at the University of Guelph and the Hospital for Sick Children in Ontario created a genetically modified mouse expressing too much of an enzyme known as PAD2. They found that these mice had significant loss of myelin, and also have behavioral deficits, such as abnormal movement, balance, and coordination.

    Not only does this work present a new mouse model to study demyleinating disease, but it also stresses the importance of PAD in maintaining myelin integrity. Their work highlights PAD as a potential therapeutic target, as well as a potential marker for early detection of MS and other diseases characterized by a loss of myelin.

    Source: EurekaAlert! (06/11/08)

    Collaborative Drug Discovery and Myelin Repair Foundation Announce Partnership
    Collaborative Drug Discovery, Inc. (CDD) announced today that its web-based software, which organizes preclinical research data to help scientists advance new drug candidates, has been selected by the Myelin Repair Foundation (MRF) to enable the foundation's sponsored researchers to collaborate more effectively.

    MRF's Accelerated Research Collaboration(TM) (ARC(TM)) model creates a unique partnership between academic researchers, scientific and drug discovery advisors and a centralized management team to define and execute on an integrated research plan that will reduce the time to market for a wide range of patient treatments. Focused exclusively at this time on identifying myelin repair drug targets that will lead to treatments for multiple sclerosis by 2009, MRF provides the business infrastructure for a team of some 30 scientists, working together virtually, from different university laboratories in the U.S. By following best business practices, working on a common research plan, sharing their findings in real time, and piggybacking experiments that might otherwise have taken years to accomplish, the scientists have been able to considerably accelerate their research.

    CDD enables scientists to collaborate easily across institutional and disciplinary boundaries and empowers new cooperative research strategies, such as MRF's innovative ARC model. The database features the ability to share data with a spectrum of permissions-either selectively with just a few specific colleagues, openly with the entire scientific community, or not at all. This flexibility encourages data sharing where appropriate while protecting intellectual property, so promising approaches can be patented and commercialized.

    The software excels at capturing and organizing fragmented data that would otherwise remain dispersed across multiple laboratories. Foundations can easily set-up and manage collaborations involving multiple research groups located anywhere in the world and spanning multiple scientific disciplines. The central database maintains research continuity as participants change and ensures continued access to the results of sponsored research. CDD manages all the infrastructure and presents data to researchers through an intuitive web interface; contextually-aware hyperlinks steer scientists where they need to go without requiring them to master complex tools.

    "By working together with CDD, we can fully exploit the value of the preclinical research data generated by our sponsored researchers and advance promising new therapies for multiple sclerosis more rapidly into clinical trials," said MRF Chief Operating Officer Rusty Bromley. "CDD's software perfectly complements MRF's Accelerated Research Collaboration model which relies on multiple groups located throughout the country, each focusing on different aspects of the overall research challenge. Each group contributes different types of data to the collaboration depending on its distinct scientific specialty. CDD's software integrates these efforts, so a virtual network of academic laboratories can drive toward developing new therapies with a degree of focus historically unavailable in academic laboratories."

    In addition to making its existing capabilities available to all MRF researchers, CDD will extend the software's range to include target validation and customize the interface for MRF's researchers. "We are delighted to enter into this partnership with MRF," said CDD Founder and President Barry Bunin. "MRF has pioneered a research paradigm that organizes diverse academic groups into highly-structured collaborations with a sharp focus on outcomes. CDD's software was designed specifically to encourage and support this type of research model, so we believe our database will significantly accelerate MRF's efforts."

    MRF and CDD will also work together to help other disease research organizations realize the full potential of collaborative research. "While MRF is specifically focused on speeding myelin repair discoveries that will lead to treatments for multiple sclerosis, we believe that our ARC model has implications for research more broadly," said Bromley. "Part of our mission is to enable others to reap the benefits of the ARC model for preclinical drug discovery R&D. A successful partnership with CDD will offer proof of concept to others seeking collaboration tools for similar research efforts."

    Source: Collaborative Drug Discovery, Inc. (28/05/08)

    Preclinical Study Published in Nature Medicine Shows Anti-LINGO-1 Antibody Promotes Remyelination
    Biogen Idec announced today the publication of findings from a preclinical study reporting that the anti-LINGO-1 antibody can promote spinal cord remyelination and axonal integrity, suggesting a potential role as a treatment for multiple sclerosis (MS) and other demyelinating diseases of the central nervous system (CNS). The results are published in the October issue of Nature Medicine, and confirm previously published data that suggested a role for the anti-LINGO-1 antibody in CNS myelin repair.

    LINGO-1 appears to act as a molecular switch that controls the ability of cells in the CNS to produce myelin, the protective cellular sheath surrounding nerve fibres that assists nerves in conducting electrical impulses. When myelin is damaged by autoimmune diseases such as MS, nerve cells lose their ability to send signals to the body. As this damage progresses, these cells may eventually die, contributing to disability. Although MS therapies can slow the progression of this damage, none are able to repair the lost myelin.

    Biogen Idec scientists had previously discovered that LINGO-1 may act to prevent myelin repair after injury. In the study published today, by blocking LINGO-1, scientists were able to promote myelin repair and improve recovery in an animal model of MS. "While preliminary, these findings are encouraging and suggest that the anti-LINGO-1 antibody has the potential to repair some of the damage caused to the CNS. This may be an entirely new approach to treating MS,” said Alfred Sandrock, MD, PhD, Senior Vice President, Neurology Research and Development, Biogen Idec. "The anti-LINGO-1 program is a key part of our research and development efforts in MS. We have a diverse pipeline of therapeutic candidates targeting multiple pathways and patient needs with the goal of offering a portfolio of options for people living with this devastating disease.”

    In the study, functional recovery from demyelination was modeled by tracking the disease progression of experimental autoimmune encephalomyelitis (EAE), a widely accepted animal model for studying the clinical and pathological features of MS. The anti-LINGO-1 antibody was administered before disease onset and was found to decrease the severity of EAE across all stages of disease progression, when compared to the control treatment group. In a related study, anti-LINGO-1 antibody treatment resulted in significantly reduced EAE symptoms even when it was administered after disease onset.

    The study found that functional recovery, as measured by EAE scores, correlated with improved axonal integrity and axonal remyelination. Physiological improvements in axonal integrity were revealed by magnetic resonance DTI imaging. At the cellular level, the production of new myelin sheaths was revealed by histological staining and electron microscopy. "This is a very exciting early indication that therapies targeted at myelin repair within the CNS can have a dramatic effect on behavioral functional outcome in models of multiple sclerosis, and opens the door for the identification of additional regulators of myelin repair that might be used to enhance functional recovery in patients with MS,” said Robert H. Miller, PhD, Principal Investigator, Myelin Repair Foundation and Director of the Center for Translational Neuroscience, Case Western Reserve University.

    Anti-LINGO-1 was discovered by Biogen Idec and is one of several programs in the company’s industry-leading research and development efforts in MS.

    In addition to its two marketed products, the company has four programs in clinical development for the treatment of MS.

    Source: Biogen Idec (01/10/07)

    Remyelination can be extensive in multiple sclerosis despite a long disease course
    Patani R, Balaratnam M, Vora A, Reynolds R. Department of Cellular and Molecular Neuroscience, UK MS Tissue Bank, Division of Neuroscience, Imperial College London, Charing Cross Hospital Campus, London, UK.

    Experimental studies using models of multiple sclerosis (MS) indicate that rapid and extensive remyelination of inflammatory demyelinated lesions is not only possible, but is the normal situation. The presence of completely remyelinated MS lesions has been noted in numerous studies and routine limited sampling of post mortem MS material suggests that remyelination may be extensive in the early stages but eventually fails. However, visual macroscopic guided sampling tends to be biased towards chronic demyelinated lesions.

    Here we have extensively sampled cerebral tissue from two MS cases to investigate the true extent of remyelination. Sections were cut from 185 cerebral tissue blocks and stained with haematoxylin and eosin (H&E), luxol fast blue and cresyl fast violet (LFB/CFV) and anti-myelin oligodendrocyte glycoprotein, human leucocyte antigen-DR (HLA-DR) and 200 kDa neurofilament protein antibodies. Demyelinated areas were identified in 141 blocks, comprising both white matter (WMLs) and/or grey matter lesions.

    In total, 168 WMLs were identified, 22% of which were shadow plaques, 73% were partially remyelinated and only 5% were completely demyelinated. The average extent of lesion remyelination for all WMLs investigated was 47%. Increased density of HLA-DR(+) macrophages and microglia at the lesion border correlated significantly with more extensive remyelination.

    Results from this study of two patients with long standing disease suggest that remyelination in MS may be more extensive than previously thought.

    Source: Neuropathol Appl Neurobiol. 2007 Apr 18

    TIGM inks deal for mice
    The Texas Institute for Genomic Medicine (TIGM) has entered into an agreement with the Myelin Repair Foundation to supply genetically altered mice that United States and Canadian researchers will use to search for the causes of and possible treatments for multiple sclerosis.

    TIGM is a Houston-based nonprofit biotech entity founded in 2005.

    The Myelin Repair Foundation, headquartered in Saratoga, Calif., is a nonprofit organisation focused exclusively on studying myelin, the protective insulation surrounding nerve fibres of the central nervous system.

    Under the terms of the agreement, TIGM will create up to 15 pairs of custom-designed "knockout mice" -- mice that have specific genes altered for myelin research that scientists are conducting at five different locations over the next year.

    The MRF has established an accelerated research collaboration process to bring together leading neuroscientists from universities throughout North America to figure out how myelin is created and damaged and how it can be repaired.

    Through this non-traditional collaborative process the MRF hopes to bring treatments for multiple sclerosis and other neurological diseases to the public more quickly.

    "By getting knockout mice into the hands of MRF researchers at an accelerated pace, TIGM can support MRF in their race to find breakthrough cures for MS," said Dr. Richard Finnell, TIGM executive director.

    "TIGM has unique technology to produce the knockout mice we need far more efficiently than we could do it in our own labs," said Rusty Bromley, MRF's chief operating officer.

    Source: Houston Business Journal © 2007 American City Business Journals, Inc

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