Mar 05, 2012
National MS Society Research News
The full text of each research article is available below the links.
- Cleveland Clinic's Dr. Richard Ransohoff Wins 2012 John Dystel Prize for MS Research -- Provided far-reaching insights on immune activity in the central nervous system
- Small Trial of Patients' Own Adult Stem Cells Appears Safe and Hints of Benefit
- Rehabilitation Technique Improves Memory and Increases Brain Activity in People with MS
- Pivotal Meeting Probes MS Therapy Use in Children
- MS Trial Alert: Pain Study Recruiting People with MS Nationwide
Cleveland Clinic's Dr. Richard Ransohoff Wins 2012 John Dystel Prize for MS Research -- Provided far-reaching insights on immune activity in the central nervous system
Feb 21, 2012
Professor Richard M. Ransohoff, MD, of the Cleveland Clinic’s Lerner Research Institute and Mellen Center for MS Treatment and Research, has been chosen by a committee of his peers to receive the National MS Society/American Academy of Neurology’s 2012 John Dystel Prize for Multiple Sclerosis Research. Dr. Ransohoff is being honored for pioneering work in MS that led to new insights on immune activity in the brain and spinal cord (neuroimmunology) , particularly the role of messenger proteins known as “chemokines.” The $15,000 prize is being presented at the annual meeting of the American Academy of Neurology in New Orleans in April.
“Dr. Ransohoff has been a galvanizing figure in neuroimmunology research and a true thought leader,” said Benjamin M. Segal, MD (University of Michigan) and Thomas Lane, PhD (University of California, Irvine), who nominated Dr. Ransohoff to receive the Dystel Prize. “The insights that Dr. Ransohoff’s discoveries have provided could ultimately pave the way for the development of a new class of drugs in MS based on chemokines.”
Dr. Ransohoff’s contributions: Dr. Ransohoff’s most far-reaching research contributions are in applying the study of the role of chemokines – (pronounced KEEmoekynz) messengers that act as attractants – in the immune attack on the brain and spinal cord that occurs in MS. In 1993, Dr. Ransohoff discovered that astrocytes – star-shaped brain cells known for supporting the brain’s structure – actually produced chemokines that attracted immune cells to move toward the brain in mice with MS-like disease. (The FASEB Journal 1993;7(6):592-600) He extended these studies to investigate chemokines in immune cells that were isolated from people with MS, meticulously analyzing MS tissues. His results showed that cerebrospinal fluid levels of specific chemokines were in fact altered during MS attacks, and the docking sites for these proteins were detected on numerous cells involved in the immune response. (The Journal of Clinical Investigation 1999;103(6):807-815)
Dr. Ransohoff has also shown that chemokines may actually help determine whether nervous system repair occurs during the course of MS. He studied immature cells that make myelin, called oligodendrocyte progenitor cells (OPCs). Myelin surrounds and supports nerve fibers and is a target of the immune attacks in MS. Along with colleague Robert Miller, PhD, Dr. Ransohoff showed that deactivating a docking site or receptor for chemokines, called “CXCR2,” improved the development of rodent OPCs and allowed for myelin repair.(The Journal of Neuroscience 1998;18(24):10457-10463) Dr. Ransohoff has continued to research CXCR2 and his findings indicate it to be a promising target for therapeutic strategies aimed at stimulating nervous system repair. Administering an antibody that blocks CXCR2 improved myelin repair in mice with MS-like myelin damage. (The Journal of Neuroscience 2010;30(27):9074-83)
CXCR2 is a drug target with compounds in clinical trials for indications other than MS, so these findings may lead to innovative strategies that address both the immune attack and myelin damage in MS. Dr. Ransohoff’s research indicates that chemokine receptors like CXCR2 are present and functional on both immune cells and resident brain cells. He is now funded by a research grant from the National MS Society to study different cell types with and without chemokine receptors to clarify how some of these cells participate in tissue damage and – importantly – tissue repair. This novel approach should lead directly to effective new therapeutic approaches to stop damaging disease activity in MS.
Sharing knowledge: Dr. Ransohoff is a world leader in translational neuroimmunology, authoring several books and more than 300 publications in peer reviewed journals. He has served on many advisory boards, including the National MS Society’s National Clinical Advisory Board and previously, serving as chair of one of the Society’s Scientific Peer Review Committees. In 2009, Dr. Ransohoff was honored for his service to the Society’s Ohio Buckeye Chapter with induction into the Society’s National Volunteer Hall of Fame. His has served on the chapter's Board of Trustees and chaired its Clinical Advisory Committee.
Dr. Ransohoff is sought after to speak about neuroimmunology, and has provided hundreds of invited lectures and presentations worldwide since 1997. He organized the first NIH/NINDS “Workshop on Chemokines and MS” and recently was invited to chair the Nervous System section of the Cell Press Inaugural Symposium on “Inflammation and Disease.” Dr. Ransohoff reviews papers for numerous peer reviewed medical journals. He introduced a Clinical Neuroimmunology section into The Journal of Neuroimmunology, served as a Highlights Editorial Advisor for Nature Reviews Immunology (2006-2011), and currently serves on the Editorial Advisory Board for Trends in Immunology, and as Associate Editor of Neurology.
Early in his career, Dr. Ransohoff received a Harry Weaver Neuroscience Scholarship from the National MS Society and a Clinical Investigator Development Award from the National Institutes of Health. He also has been repeatedly listed in the “Best Doctors in America.” Dr. Ransohoff has mentored dozens of young men and women who are engaged in scientific research, or serving as practicing neurologists, around the globe.
About the Prize: The $15,000 Dystel Prize is given jointly by the National MS Society and the American Academy of Neurology, and is funded through the Society’s John Dystel Multiple Sclerosis Research Fund. Society Honorary Life National Board of Directors member Oscar Dystel and his late wife Marion established this fund in 1994 in honor of their son John Jay Dystel, an attorney whose promising career was cut short by progressive disability from MS. (John died of complications of the disease in June 2003.) Previous winners of the Prize are Drs. Donald Paty (1995), Cedric Raine (1996), John Kurtzke (1997), Henry McFarland (1998), W. Ian McDonald (1999), Kenneth Johnson (2000), John Prineas (2001), Stephen Waxman (2002), Bruce Trapp (2003), Lawrence Steinman (2004), Jack Antel (2005), William Sibley (2006), Howard Weiner (2007), Stephen Hauser (2008), David Miller (2009), David Hafler (2010), and Brian Weinshenker (2011). Read more about other Dystel Prize winners.
Biography: Dr. Ransohoff is Director of the Neuroinflammation Research Center in the Department of Neurosciences of Lerner Research Institute at the Cleveland Clinic Foundation; Staff Neurologist in the Foundation’s Mellen Center for MS Treatment and Research; Professor of Molecular Medicine at the Foundation’s Lerner College of Medicine; and Professor in the Department of Pathology at Case Western Reserve University. Dr. Ransohoff received his undergraduate degree in literature from Bard College and his medical degree with honors from Case Western Reserve University School of Medicine in Cleveland. He completed residencies in internal medicine at Mt Sinai Medical Center in Cleveland and in neurology at Cleveland Clinic, where he served as Chief Resident. Dr. Ransohoff completed a postdoctoral fellowship in the laboratory of Dr. Timothy Nilsen in the Department of Molecular Biology and Microbiology at Case Western Reserve University School of Medicine. He joined the faculty of the Cleveland Clinic in 1984.
Small Trial of Patients' Own Adult Stem Cells Appears Safe and Hints of Benefit
Feb 15, 2012
Results of a clinical trial involving 10 people with secondary-progressive MS suggest that injecting a person’s own bone marrow stem cells (mesenchymal cells) appears safe and may be beneficial in helping to protect the nervous system from injury from MS. Further trials now underway should further establish the safety and potential benefit of this approach for treating MS. The study, by Drs. Peter Connick (University of Cambridge), Siddharthan Chandran (University of Edinburgh) and colleagues, was published in the February Lancet Neurology (2012; 11:150-156).
Background: There are many types of stem cells that are undergoing varying degrees of research and which are producing knowledge about their potential usefulness for treating MS. Further study is necessary to determine what kind of cells might prove optimal for treating some or all people with MS.
One approach to stem cell research in MS relates to efforts to repair nervous system damage, or to protect against the damage (neuroprotection). This research is in its infancy, and there is no evidence yet that any type of stem cells can reverse MS damage or protect against it. Adult mesenchymal (pronounced messENkimmul) stem cells are present in many tissues of the body, including the bone marrow and fat. These cells potentially have the ability both to treat immune disorders and promote tissue repair. Studies in rodent models of MS have suggested that injections of mesenchymal stem cells may have benefit, and a few trials are testing this approach in MS and in spinal cord injury.
Since there is an unmet need for therapies for progressive MS, the United Kingdom investigators chose to do this clinical trial focusing on people with secondary-progressive MS. The study was funded by many sources including the Medical Research Council, MS Society of Great Britain and Northern Ireland, and the Wellcome Trust.
The Study: Designing a clinical trial to show neuroprotection is difficult because, for one reason, the course of MS is so variable. To work around this difficulty, the research team recruited people who had very specific signs of myelin damage in the optic nerve. Participants included women and men ages 40 to 53 who had lived with MS for an average of 14.4 years. The procedure involved removing the individuals’ own bone marrow cells, which were then sorted, multiplied in lab dishes and eventually infused into the vein. Participants received a single infusion of cells based on their body weight.
The team’s primary goal was to assess feasibility and safety, but they also evaluated other outcomes such as visual function, MRI scans and disability. They observed participants for at least 12 months before the infusion and at least 6 months afterward. This small proof-of-concept trial was not placebo controlled, and the investigators compared the condition of participants for the 12 months before treatment against their condition after treatment.
Results: The procedure was found to be safe, with no serious adverse events identified. Several aspects of vision appeared to improve after treatment, including visual acuity, sensitivity to contrast, visual signal conduction (visual evoked response latency and amplitude), and optic nerve area. There was also a reduction in the rate of progression on the EDSS, a standard scale that measures physical disability. Other aspects of visual function did not change, including color vision and visual field, and imaging measures of disease activity, such as lesion volumes, retinal fiber layer thickness, and brain volume did not change significantly.
Comment: As the authors point out, the small, uncontrolled nature of the study make it important to verify the results in larger, controlled trials. In an accompanying editorial, Drs. Mark Freedman and Antonio Uccelli, who established the International Mesenchymal Stem Cell Transplantation Study Group, note that although the study is not definitive, it raises substantial interest because of the signs of repair shown in participants with secondary-progressive MS. Further trials now underway should further establish the safety and potential benefit of this approach for treating MS.
This study emphasizes the importance of research to restore function in MS by repairing and protecting the nervous system. Read more.
Rehabilitation Technique Improves Memory and Increases Brain Activity in People with MS
Feb 14, 2012
In a small, controlled study, learning and memory improved in people with MS with a technique that uses stories and imagery to cement learning. For the first time, this improvement was shown to be accompanied by biological changes in the brain indicating increased activation of areas related to memory and learning. Nancy D. Chiaravalloti, PhD, John DeLuca, PhD (Kessler Foundation Research Center) and colleagues report their findings in The Journal of Neurology (Published online, January 12, 2012). Victoria Leavitt, PhD – a postdoctoral fellow funded through the National MS Society’s Mentor-Based Postdoctoral Fellowship program – presented preliminary findings from this study at ECTRIMS 2011 and earned an award for the team’s poster presentation. The study was also funded by the National MS Society, the National Institutes of Health and the Kessler Foundation.
Background: Cognitive changes are common in people with MS. Certain functions are more likely to be affected than others, such as memory (acquiring, retaining, and retrieving new information). Researchers are investigating ways to restore function in people with MS who experience cognitive problems, including cognitive rehabilitation techniques.
Kessler Foundation designed a fellowship program to train post-doctoral fellows to conduct such research in neuropsychology, cognitive rehabilitation and cognitive/translational neuroscience. This program is funded through the National MS Society Mentor-Based Postdoctoral Fellowship in Rehabilitation Research, which aims to recruit and train talented clinician-scientists in rehabilitation research specific to MS.
The Study: The team recruited 16 people with MS, and administered neuropsychological assessments and functional magnetic resonance imaging (fMRI). fMRI allows researchers to take active images of the brain while the person is performing memory tasks that require them to learn a list of words or a short story. Participants were then randomly assigned to undergo 10 treatment or placebo sessions, twice a week for five weeks. In the treatment sessions, participants were trained using the modified Story Memory Technique (mSMT), which helps people to learn new information and remember older information using imagery and context. The technique is applied to real-life situations, such as remembering a shopping list or a list of errands. A control group met for 10 sessions as well, working on the same tasks, but by reading and answering questions. Neuropsychological and fMRI assessments were repeated after the sessions were completed.
The results show that the treatment group improved by more than 10% over the control group in the ability to recall information. For the first time, the team was also able to show that fMRI scans revealed increased activation in all participants in the treatment group in areas of the brain related to learning and memory. The fMRI scans did not change after the sessions in the control group.
Comment: This innovative study identifies regions of the brain associated with improvements in learning and memory, and suggests that further research might help to develop therapeutic strategies that increase activation of these regions – and thus increase learning and memory. The authors note that such strategies might use mSMT in combination with pharmacological treatment for maximized effect.
“These findings are a great example of why we need to increase rehabilitation research,” says Nicholas LaRocca, Vice President of Health Care Deliver and Policy Research for the Society. “We need to show that rehabilitation interventions can restore function in people with MS – conclusively – to health care providers and payers. Our fellowship program is helping us to reach this goal.”
The National MS Society’s Strategic Response to MS emphasizes a focus on rehabilitation research aimed at restoring function and improving quality of life. Read more about this research.
Pivotal Meeting Probes MS Therapy Use in Children
Feb 13, 2012
There are eight MS therapies that reduce MS activity, and even more under study – how can we safely study them in children who have MS? This was the focus of the “Emerging Therapies Summit,” a workshop convening representatives from drug regulatory agencies, MS advocacy organizations, pharmaceutical companies and pediatric MS experts, held by the International Pediatric MS Study Group (IPMSSG) and funded by the National MS Society and the MS International Federation. A report from the meeting will be published and a Clinical Trials Task Force is being created by the IPMSSG to drive consensus around designing and conducting trials in children.
Background: Although MS occurs most commonly in adults, it is also diagnosed in children and adolescents. Estimates suggest that 8,000-10,000 children (defined as up to 18 years old) in the United States have multiple sclerosis, and another 10,000-15,000 have experienced at least one symptom suggestive of MS. Increasing evidence suggests that the disease-modifying therapies are safe and well tolerated in children. However, clinical trials have not formally evaluated the safety or effectiveness of these therapies in children with MS.
Regulatory agencies are increasingly mandating that these trials are necessary when developing new therapeutic strategies for which pediatric use is anticipated. As a voluntary group of over 150 academic physicians and researchers treating and/or studying MS in children, the IPMSSG deemed the time right for a summit to consider the feasibility of trials in pediatric MS.
The Meeting: The IPMSSG amassed a capable group: More than 70 people from the academic and clinical pediatric MS field, representatives from three regulatory agencies (the U.S. Food and Drug Administration, the European Medicines Agency and Health Canada), members of MS patient organizations, and staff from seven pharmaceutical companies (both manufacturers of approved therapies and of experimental treatments in the MS pipeline) attended the summit.
The primary goal of the meeting was to analyze the feasibility, methodology, and priorities for pediatric clinical trials of new therapeutic strategies in MS. The group discussed current knowledge and best practices in several areas, including clinical outcome measures, clinical trial design, imaging outcomes, cognitive outcomes, pharmacology, drug safety and biological mechanisms, and drug safety registries.
Next steps: A comprehensive meeting report will be published in the near future, and a Clinical Trials Task Force is being created by the IPMSSG to drive consensus around the complicated process of designing and conducting trials in children. The goal is to ensure that advances in the treatment of MS in children are achieved in the shortest possible time frame with the highest degree of safety.
The National MS Society is a driving force in the effort to study MS in children, with the hope of stopping the disease in its tracks in the youngest people who have it, and the hope that understanding the disease in its earliest stages will help to end MS forever. Read more about pediatric MS and the network of Pediatric MS Centers of Excellence established by the Society.
MS Trial Alert: Pain Study Recruiting People with MS Nationwide
Feb 07, 2012
Summary: Investigators nationwide are recruiting 400 people with secondary-progressive MS or relapsing-remitting MS to compare the effectiveness of three doses of the oral drug AVP-923 (Nuedexta®, dextromethorphan hydrobromide and quinidine sulfate, Avanir Pharmaceuticals) or inactive placebo in reducing central neuropathic pain. The study is funded by Avanir Pharmaceuticals.
Rationale: Studies suggest that half of people with MS experience pain. There are two types of chronic pain experienced by people with MS: central neuropathic pain (caused by nerve damage) and non-neuropathic pain (caused by muscle spasms or contractions). Central neuropathic pain is often described as burning, stabbing, and shooting pain in the legs and arms; and numbness, tingling, prickly, or “pins and needles” sensations. The purpose of this study is to evaluate the investigational use of AVP-923 to determine if it reduces central neuropathic pain experienced by those with MS.
AVP-923 is a patented, orally-administered combination of dextromethorphan and an enzyme inhibitor known as quinidine. Quinidine slows down the breakdown of dextromethorphan in the body, which results in a sustained elevation of dextromethorphan in the brain. Marketed as Nuedexta®, the drug is approved to treat pseudobulbar affect (uncontrolled episodes of crying and or laughing that are disconnected from or out of proportion to what the person is feeling at the time) in people with MS and other neurological diseases. Based on its biological activity within the central nervous system, the drug is being evaluated for its potential impact against pain as well.
Eligibility and Details: Participants should be ages 18 to 85, with a diagnosis of relapsing-remitting or secondary-progressive MS, and a clinical history or symptoms of central neuropathic pain. Because AVP-923 may cause serious side effects including changes in heart rhythm, participants with certain cardiac conditions are excluded from the study. For more details about enrollment criteria, please contact the study site nearest you.
Participants are being randomly assigned to receive one of three AVP-923 doses or inactive placebo (taken as one capsule twice a day) for 12 weeks. Participants have 75% chance (3 out of 4) of receiving AVP-923 and 25% chance (1 out of 4) or receiving placebo. The primary goal of the study is to determine whether pain symptoms are reduced, by using the Pain Rating Scale. Secondary endpoints include improvements in clinical scales that measure fatigue, MS disease activity, sleep quality and depression.
Contact: To learn more about the enrollment criteria for this study, and to find out if you are eligible to participate, please contact the study site nearest you. The list of recruiting sites can be found on clinicaltrials.gov.
Nuedexta is a registered trademark of Avanir Pharmaceuticals, Inc .