National Multiple Sclerosis Society
Meet the Researcher:
Oksenberg KleinNew Center Awards: 17 New Pilot ProjectsResearch Areas: Collaborative MS Research Center Awards
The National Multiple Sclerosis Society has just committed $12.4 million to support 23 new MS research projects with terms running up to five years. These projects were found to be of the highest scientific merit and significance in the fight against MS, out of scores reviewed by our volunteer panel of scientific advisors.
This commitment includes $3.3 million to support four new Collaborative MS Research Centers, a program launched in 2003 to speed the search for the cause of, and cure for, MS. The new Center Awards are described on pages 9-12.
When research commitments are made, the money is not in hand to meet them: The Society now has over $50 million in current- and future-year commitments to meet. Money must be raised each year to fulfill them. Contributions to the Society to help support these committed projects are essential to help us meet our financial obligations.
The new research projects are part of a research program that is slated to invest more than $30 million this year alone to advance MS research, including funding over 300 new and ongoing MS investigations in the U.S. and abroad. By the end of this year, the Society will have invested a total of $420 million since its founding to support basic and clinical research aimed at finding a cure for MS.
Following are brief summaries of the new research grants, grouped according to major avenues of MS investigation. In addition, 17 new “high-risk” projects aimed at testing innovative ideas were awarded over the last six months through the Pilot Research Program. These are listed on page 6.
Seeking Better Ways to Manage MS
Ultimately, the goal of the biomedical research program of the National MS Society is to develop therapies – both medications and rehabilitation programs – that will combat the course or symptoms of MS. The goal of a rehabilitation program is to restore functions essential to daily living. Rehabilitation programs can have several different aspects, including physical therapy, occupational therapy, speech therapy, or cognitive retraining.
The Society supports such efforts by providing financial support to investigators testing novel methods of tracking and treating MS symptoms with rehabilitation programs.
The Society is currently spending $1.9 million to fund 10 research projects tracking the effects of rehabilitation, including the following new clinical study.
Region: Greater North Jersey Chapter
Award: Research Grant
Term/Amount: 4/1/04-3/31/07; $428,372
“Working memory in MS: Using fMRI toidentify the deficit”
Correlating memory difficulties with brain activity to understand how to overcome such difficulties in MS. Many people with MS report difficulties with attention, concentration, and memory.
Nancy D. Chiaravalloti, PhD, and colleagues have shown that deficits in “working memory” may be the source of some cognitive difficulties. Working memory refers to the ability to hold and manipulate information in the brain (e.g., add numbers without writing them down).
Now, Dr. Chiaravalloti's team is seeking to identify more precisely how working memory may be impaired in some people with MS. Working memory involves two processes: holding information in the brain and manipulating this information.
The investigation involves 20 people with MS who have an impairment in working memory; 20 people with MS without working memory impairment; and 20 people without MS. Participants are undergoing neuropsychological assessment and functional magnetic resonance imaging (fMRI).
fMRI allows researchers to take active images of the brain while it is performing working memory tasks that require either maintaining or manipulating information. The patterns of activation between the groups will be compared to identify specific sites in the brain responsible for working memory deficits in MS.
Results of this study will help us to better understand the source of working memory deficits in people with MS, and improve our ability to track changes in working memory, especially as a result of treatment.
Who is Susceptible to MS?
Research suggests that MS occurs in individuals and in families whose genes make them susceptible to developing the disease, but evidence indicates that MS is a “multigenic” disease, meaning that many separately inherited genes contribute to MS susceptibility. Although this has made searching for the genes more complex, investigators are taking many approaches and are making exciting headway.
In September 2003, the Society and the National Institutes of Health brought together top genetics experts to review current efforts to discover MS genes, and to evaluate how progress can be expedited in this exciting field. As a result of the meeting, new strategies are now under consideration to speed this search. Three newly funded projects focus on MS genes.
Region: Central New England Chapter
Award: Research Grant
Term/Amount: 4/1/04-3/31/07; $670,788
Funded by the NMSS Central New England chapter, in part by gifts from Barbara Palmer.
“A whole genome admixture scan for themultiple sclerosis genes”
Scanning for MS genes in genetic material from patients whose ancestry contain a mix of populations at high risk and at low risk for MS. Although MS is not inherited directly, there appears to be a genetic predisposition to developing the disease. Evidence indicates that a single gene alone does not determine the risk of getting MS. Many separately inherited genes appear to contribute to MS susceptibility, making the search more complex. David A. Hafler, MD, is using a new and powerful technique called “admixture mapping” to identify MS genes.
As it relates to MS, admixture mapping involves studying the genetic basis of MS in populations with mixed racial ancestry. MS in African-Americans is clinically similar to that seen in European-Americans (Caucasians). However, African-Americans have only one-half the risk of developing MS when compared to those of European extraction. Continental Africans have an even lower rate of MS than African-Americans. These facts suggest that genetic susceptibility to MS in African-Americans may lie in the genetic material that might have been inherited from a European ancestor.
Dr. Hafler’s team is studying genetic material from 1000 African-Americans with MS, collected by Jorge Oksenberg, PhD, and Stephen Hauser, MD (University of California at San Francisco) with separate funding from the National MS Society. They are identifying which parts are of European ancestry, and are looking for small overlapping regions that may contain MS genes. This study should help to identify MS genes in African-Americans and in the general population as well, and may provide targets for the development of new drugs for MS.
Region: New York City Chapter
Award: Research Grant
Term/Amount: 4/1/04-3/31/06; $632,251
“Variants of beta-chemokines within chromosome 17q11 in MS”
Searching for possible gene variations in a specific chromosome region that may account for increased susceptibility to MS.
Multiple genes are thought to be involved in making individuals susceptible to MS, although the disease is not directly inherited. Researchers have found evidence that one of these genes might exist on chromosome 17, in a region of genes (17q11) associated with the control of messenger proteins, called “chemokines,” that help orchestrate the immune attack in MS.
Bernadette Kalman, MD, PhD, is attempting to identify which chemokine genes located in 17q11 might be involved in MS susceptibility. Her team is studying 300 families affected by MS, looking for genetic variations called SNPs (single nucleotide polymorphisms). SNPs are markers, or indicators that a gene related to a given trait may be nearby. They are comparing results between families affected by relapsing-remitting, secondary- progressive and primary-progressive MS.
This study may provide an important piece of the complex puzzle of MS susceptibility. When that puzzle is solved, we will know more about the cause of the disease and have better clues to preventing and treating it.
“Genetic mapping in multiple sclerosis”
Attempting to pinpoint genes that may be involved in determining MS susceptibility, progression and other disease characteristics. Researchers believe that multiple genes – the coded instructions for all of the body’s activities – help determine a person’s susceptibility to developing MS. Genes are packaged in ribbon-like chromosomes within most cells. As part of a National MS Societysupported genetics research team, Jorge R. Oksenberg, PhD, previously identified multiple regions of the chromosomes that may contain candidate MS susceptibility genes.
Now Dr. Oksenberg is building on this information to further pinpoint the exact location of these candidate MS genes and to determine their exact role in the disease, using genetic samples from families with MS from many different populations. The team is also determining whether certain clinical characteristics – such as age at MS onset, disease course, and time to progression – are linked to specific genetic variations. This project should yield important information regarding the genetic basis of MS susceptibility, which could be used to identify at-risk individuals and provide insights into new treatment approaches.
The researchers who tackle the complicated field of MS genetics must be well armed in their training. Jorge R. Oksenberg, PhD (University of California at San Francisco, UCSF) received his PhD in Immunology in 1987 from Hebrew University in Jerusalem, and has been involved since then in MS research. He joined the UCSF faculty following a Society-funded postdoctoral fellowship at Stanford University. He now is analyzing genetic factors that affect susceptibility to MS and the course of disease.
“We can see that MS has a strong genetic component partly because an individual's risk of developing MS increases several-fold if a close family member has MS, and the disease occurs more frequently in some ethnic populations (Northern Europeans) compared with others (African and Asian groups),” he says. Dr. Oksenberg is deeply involved in the Society-supported MS Genetics Group, a collaboration of scientists at UCSF, Vanderbilt University, and Duke University.
Dr. Oksenberg’s team recently reported an association between a sequence of immune system-related genes and MS in African-Americans (American Journal of Human Genetics, January 2004). His latest project extends these efforts farther. “We recently completed our second screen of the entire genome (all the genetic material in humans) to identify segments that might be linked to MS susceptibility,” he says. “Now we are examining segments we identified in detail to determine the exact location of MS genes. “Finding these genes can transform current thinking about the disease,” says Dr. Oksenberg. “It is possible that new genetic knowledge could implicate an unexpected biological pathway in the development of MS, immediately guiding research into treatment, and perhaps even leading to prevention of the disease.”
Read more about this project above.
What Starts the MS Attack?
For years, researchers have been searching for evidence that a virus or other microbe could be the culprit, not by directly causing MS – which is not an infectious disease – but possibly by fouling up immune responses such that the body’s brain and spinal cord tissue is mistaken for an outside invader.
The National MS Society has current, multi-year commitments of nearly $1.4 million to support 7 research projects focusing on understanding the role of infectious triggers in MS, including this new project.
Region: Iowa Chapter
Award: Research Grant
Term/Amount: 4/1/04-3/31/07; $393,971
“Pathogenesis of MHV-induced demyelination in RAG1-/- mice”
Determining immune mechanisms involved in myelin destruction in a viral-induced model of MS, in search of improved therapies for MS. In MS, a misdirected immune response damages nerve-insulating myelin. An infection in mice caused by the mouse hepatitis virus (MHV) results in similar immune-mediated myelin damage, and thus serves as a good model to study MS.
Stanley Perlman, MD, PhD, is experimenting with a mouse that lacks the necessary B and T cells to generate a rigorous immune response. This mouse does not develop MS-like disease in response to MHV unless specific immune cells are “added in” from normal mice. Using this model, Dr. Perlman’s team can explore the roles of different parts of the immune system in the steps that lead to myelin destruction similar to MS. In this study, they are focusing on the immune messenger interferon gamma, as well as antibodies and scavenger cells.
These experiments should help answer key questions about major players in the immune attack in MS, and could generate future studies aimed at stopping the cascade of immune events before they lead to MS.
Over the last six months, 17 new grants were awarded through the Pilot Research Program. These projects are aimed at quickly exploring new, untested ideas and generating preliminary data needed to apply for full grant support.
Michael Baime, MD “Mindfulness-based stress management for people with MS andtheir caregivers” University of Pennsylvania, Philadelphia $44,000; 02/01/04-01/31/05
Ernesto Bongarzone, PhD "Enhancing the capacity of neural stem cells to generate oligodendrocytes” Fondazione Centro San Raffaele, Milan, Italy, $40,000; 09/30/03-09/30/04
Angelique Bordey, PhD “Ion channels and GABA receptors in glial progenitors of thesubventricular zone” Yale University, New Haven, CT, $44,000; 01/01/04-12/31/04
Deborah Clawson, PhD “Prospective memory and the effect of a mnenomic strategy inMS” The Catholic U. of America, Washington, DC, $44,000; 12/01/03-11/30/04
Ian Duncan, PhD “The expression of axon regeneration inhibitors in myelin mutant rats” University of Wisconsin-Madison, Madison, WI, $44,000; 09/30/03-09/30/04
Robert Eckel, MD "Lipoprotein lipase and nerve myelination” University of Colorado Health Sciences Center, Denver, CO, $44,000; 11/01/03-10/31/04
Michele Kosiewicz, PhD “Characterization of tolerogenic antigen-presenting cells foruse in the treatment of EAE” University of Louisville, KY, $44,000; 01/01/04-12/31/04
Andrea Lowe-Strong, PhD “The effectiveness of reflexology in the management of painin multiple sclerosis” University of Ulster at Jordanstown, Belfast, Co. Antrim, Northern Ireland, $40,000; 02/01/04-01/31/05
Jeffrey Mason, PhD “The ability of T-lymphocytes to induce axonal degeneration” Thomas Jefferson University, Philadelphia, PA, $44,000; 03/01/04-02/28/05
Matthew Meyerson, MD, PhD “Pathogen discovery by computational subtraction in multiplesclerosis” Dana-Farber Cancer Inst., Boston, MA, $44,000; 09/30/03-09/30/04
Isobel Scarisbrick, PhD “Kallikrein 6 mRNA splice variants as targets to treat CNS demyelinatingdisease” Mayo Clinic Fdn., Rochester, MN, $44,000; 12/01/03-11/30/04
Lawrence Sherman, PhD “Role of hyaluronan in inhibition of remyelination” Oregon Health & Science University, Beaverton, OR, $44,000; 02/01/04-01/31/05
Dusanka Skundric, MD, PhD “Molecular mechanisms of oligodendrocyte damage byMOG specific T cells” Wayne State University, Detroit, MI, $44,000; 11/01/03-10/31/04
David Stevens, PhD “Low cell-dose transfer of suppression in EAE” Wayne State University, Detroit, MI, $44,000; 01/01/04-12/31/04
Michael Thaut, PhD “Enhancing verbal memory in MS with music: an EEG study” Colorado State University, Fort Collins, CO$44,000; 02/01/04-01/31/05
Peter Werner, PhD “AMPA/KA receptors & blood brain barrier integrity in MS andEAE” Albert Einstein College of Medicine, Bronx, NY, $44,000; 03/01/04-02/28/05
Xiaoli Yu, PhD “Identification of MS antigens with recombinant antibodies cloned fromMS CSF B cells” U. of Colorado Health Sci. Ctr., Denver $44,000; 02/01/04-01/31/05
Can Myelin Be Repaired?
Exploring glia (which include cells that make nerve-insulating myelin, a target of the immune attack in MS) is a cornerstone of MS research. Immature myelin-making cells in the brain may be able to repair myelin. Investigators are working to decipher molecular signals that are sent out at sites of injury to recruit such cells, in hopes of finding ways to mimic these signals. Proteins known as “growth factors” are under investigation because they may help activate myelin and nerve growth. Researchers are also investigating interactions between myelin and nerve fibers, which may profoundly affect the health of both tissues.
The Society is funding 64 projects in glial cell/myelin biology, for a total multi-year commitment of some $19.6 million, including the following 4 new projects.
Award: Research Grant
Term/Amount: 4/1/04-3/31/07; $265,455
“Axoglial contacts: molecular organization and role in signaling”
Molecular controls over the formation and function of crucial sites on nerve fibers where the nerve cell and its myelin coating communicate. MS involves an immune system attack on nerve-insulating myelin and nerve fibers. Recent research indicates that understanding the so-called “axoglial” junctions where myelin and nerve fiber meet may be key to developing strategies for maintaining the health and function of both. Jean-Antoine Girault MD, PhD, and others have identified some of the molecules involved in maintaining axoglial junctions.
Dr. Girault’s team is now attempting to determine the precise molecular organization of axoglial junctions. As part of this research, they are setting up models in laboratory dishes involving components of both nerve and myelin-making cells, enabling the researchers to reproduce and carefully observe some aspects of these cells’ interactions. Understanding the principles that regulate organization of the axoglial junction is an essential step toward identifying novel approaches to preventing nerve tissue damage in MS.
Award: Research Grant
Term/Amount: 4/1/04-3/31/07; $219,750
“CNS connexins and demyelination in CMTX”
Understanding the involvement of a protein that may play a critical role in the health and damage of nerve-insulating myelin and nerve fibers.
This investigation is taking an important discovery made in one neurological disease and asking whether it holds a clue to MS. In an inherited disease called Charcot Marie Tooth disease, or CMT, a gene defect in a protein called connexin causes myelin loss in the peripheral nervous system (outside the brain and spinal cord). Within the brain and spinal cord, several types of connexins are found in myelin-making cells called oligodendrocytes, which are destroyed in MS.
Kleopas A. Kleopa, MD, is investigating whether genetic mutations – mistakes in the molecular blueprints of connexins known to be involved in CMT – might also be involved in the destruction of nerve-insulating myelin in MS.
Preliminary experiments have shown that mutations cause certain connexins to be misplaced inside the oligodendrocyte instead of reaching the surface where they are needed to properly form and maintain myelin. Now Dr. Kleopa’s team is studying the function, location, and possible interactions among different connexins in oligodendrocytes. The team is introducing connexin mutations into mice to determine how oligodendrocytes and myelin are affected.
This study may shed new light on how a cellular defect in oligodendrocytes can lead to myelin breakdown in the brain and spinal cord, and may suggest ways to compensate for myelin loss in MS.
Region: Greater Delaware Valley Chapter
Award: Research Grant
Term/Amount: 4/1/04-3/31/07; $400,382
“Excitotoxicity in experimental allergic encephalomyelitis”
The role of overstimulation of nerve and myelin-making cells in MS tissue damage, and whether it can be blocked to treat the disease.
Most current therapies for multiple sclerosis work by modulating the immune attack against nerve fiber-insulating myelin in the brain and spinal cord. Research is ongoing to develop treatments that can specifically prevent the damage to nerve fibers which also occurs, and which is associated with loss of function in people with this disease.
David Pleasure, MD, and colleagues are investigating a possible role for “excitotoxicity” in causing damage to both myelin-making cells and nerve cells in MS.
This phenomenon occurs when a natural substance, called glutamate, which is released from nerve cells to transmit nerve impulses to other cells, attaches to myelin-making cells and nerve cells, over-stimulating and killing them. Dr. Pleasure’s team is using genetically altered mice with the MS-like disease EAE to study whether administering glutamate contributes to cell death, and whether inhibiting glutamate docking activity reduces such damage. This research may demonstrate the potential of inhibiting glutamate activity as a therapeutic strategy to prevent MS progression.
Region: Central Virginia Chapter
Award: Research Grant
Term/Amount: 4/1/04-3/31/08; $547,118
“Molecular mechanisms of neurotrophin-3 action in oligodendrocytes”
Investigating factors that may regulate the ability of brain cells to develop into mature cells capable of repairing myelin destroyed by MS.
MS involves an immune system attack against the myelin coating that surrounds nerve fibers in the brain and spinal cord. MS is also characterized by the damage and death of the cells that make myelin, called oligodendrocytes. One possibility for stimulating repair of myelin in MS is to enhance the body’s natural “growth factors.” One such molecule is neurotrophin-3 (NT-3), which has been found to stimulate the proliferation and survival of oligodendrocytes, but the mechanisms involved in this stimulation are not clear.
Clarifying these mechanisms is the main objective of Carmen Sato-Bigbee, PhD. Her team has found that a protein known as CREB appears to play an important role in NT-3 activity. They are testing the idea that NT-3 and CREB regulate genes that play crucial roles in oligodendrocyte proliferation and survival. To do this, the team is using mouse oligodendrocytes isolated in the laboratory, and also is investigating oligodendrocyte function in mice models in which NT-3 has been deleted. Finding ways to manipulate these genes could protect oligodendrocytes from dying and increase their numbers.
A better understanding of factors that contribute to the health and population of myelin- making cells could help develop treatments that stimulate myelin repair in MS.
The National MS Society has just committed to funding four new, five-year Collaborative MS Research Centers, providing $825,000 each for scientists and clinicians from a variety of fields to team up on promising avenues of MS research. The new projects represent a commitment of $3.3 million to find ways to stop MS and reverse its devastating effects.
Bruce D. Trapp, PhD, Cleveland Clinic Foundation, Cleveland, Ohio
Region: Ohio Buckeye
Purpose: To identify molecules that have the potential to therapeutically stimulate the repair of myelin damaged by MS.
Dr. Bruce Trapp and colleagues helped to change the course of MS research when, a few years ago, they reported finding that brain tissue from individuals with MS showed evidence of damage not only to the myelin that coats and insulates nerve fibers, but also to the wire-like nerve fibers themselves, which normally transmit nerve signals. This work has spurred investigations leading to the idea that nerve damage can occur frequently and early in MS, and that long-standing disability associated with MS might be the result of nerve, rather than myelin, damage. It has also underscored the need to protect myelin and to repair it when it is damaged, both to maintain proper nervous system function, and to help stave off nerve fiber damage that can lead to progressive disability in MS.
The good news is that the body attempts to repair myelin damage and sometimes succeeds, especially early in the MS disease process. The aim of this Center award is to find ways to improve natural repair processes so that they do a more complete job of restoring myelin and preserving neurological functions – findings that can be applied to people with MS.
Of primary focus in this quest are immature myelin-producing cells resident in the brain which can mature into replacement myelin-making cells called oligodendrocytes, and travel to sites of MS lesions where they promote tissue repair.
The Center team is studying these “progenitor” cells in various stages of their development, in laboratory conditions and in animal models with MS-like disease.
They have two central goals:
1) to understand genetic and other signals that normally direct progenitor cells to divide and multiply and differentiate into mature cells fully capable of making myelin; and
2) through a massive screening effort, to find specific molecules that can be used therapeutically to enhance and promote formation of adult oligodendrocytes and myelin from immature cells resident in the brain.
This Center brings together four worldclass scientists to bear on these important questions: Drs. Trapp, Wendy Macklin, and Robert Miller are experts in MSrelated central nervous system development and pathology, especially related to development and function of oligodendrocytes.
Dr. Andrei Gudkov is new to MS research, and brings expertise in identifying molecular targets for cancer treatment. His work in the Center focuses on searching for small molecules that influence the survival, growth and proliferation of progenitor cells that have the inherent capacity to become replacement cells that will form new myelin. Molecules that he discovers could become the basis for therapies that protect or repair myelin in MS.
This Center will advance the field of myelin protection and repair through the collective efforts and wisdom of established scientists on a crucial MS problem.
Purpose: To define how axons, the longarm of nerve cells, are damaged in MSand search for ways to protect them.
In MS, damage to axons likely begins during the early stage of disease, and is a major cause of disease progression and disability. However, we do not know if this injury occurs secondary to damage to the myelin coating that insulates axons, or if it is a primary consequence of the immune attack on the brain and spinal cord. This has precluded the development of effective strategies to protect nerve cells in MS.
The primary goal of this Center is to define mechanisms that underlie axonal injury in MS and to develop novel therapeutic approaches to diminish disease progression. Peter A. Calabresi, MD, has brought together both established and developing scientists – many with expertise in other diseases where nerves are damaged – to focus on this damage in MS.
Dr. Calabresi is applying his own longstanding interest in defining features of the immune attack in MS to understanding the immune mechanisms that may underlie axonal injury both in cells in the laboratory and in rodent models. Avindra Nath, MD, an important contributor to the field of HIV-induced nerve damage, is using a sophisticated method of examining how human nerve, myelin-making, and immune cells interact in laboratory dishes, possibly causing axonal injury.
Collaborator John W. Griffin, MD, has expertise in nerve damage that occurs in the peripheral nervous system – outside the brain and spinal cord. He is studying rodent models of myelin damage to understand how this damage may affect axons. Team members Douglas A. Kerr, MD, PhD, and David N. Irani, MD, are translating their experiences in animal models in which myelin damage is induced by immune responses to viruses, to models more similar to MS.
To assist the translation of this laboratory research to clinical trials, Justin C. McArthur, MBBS, MPH, has joined the team. Dr. McArthur has established the infrastructure to design and conduct clinical trials, including a team of imaging experts, cognitive scientists, and a statistician. Acting as a consultant to this project is Richard T. Johnson, MD, internationally known for his knowledge and expertise in infectious and immune-mediated disorders of the nervous system, including MS. This project promises to further define how nerve cells are damaged in MS, and identify neuroprotective strategies for people with this devastating disease.
Region: Greater Connecticut Chapter
Purpose: To explore facets of tissue damagein MS and test ways to protect and repairnerve tissue, ultimately to restorefunction in persons with MS.
In MS, an immune attack is launched that wreaks havoc in the central nervous system, damaging nerve-insulating myelin and nerve fibers (axons) in the brain and spinal cord. Jeffery D. Kocsis, PhD, and colleagues have shown that injecting bone marrow cells from the thigh bone of rats into their veins repairs myelin damage induced in their spinal cords. Bone marrow (spongy tissue found in bones) contains stem cells, immature cells that are capable of giving rise to other types of cells, including myelin-making cells.
Now, with funding from a Center Award, he is applying his findings to EAE, an MS-like disease. Specifically, this team is exploring how myelin and axonal damage occurs in EAE, and whether bone marrow cell transplantation or other treatments can protect axons as well as repair myelin. This Center integrates the work of established MS researchers with outstanding scientists from other fields.
Nancy H. Ruddle, PhD, and Peter Cresswell, PhD, are part of the effort to investigate how myelin and axons are damaged in EAE. Dr. Ruddle is a noted immunologist who has contributed much to our understanding of the immune attack in MS. Dr. Cresswell is an expert on the biochemistry and cell biology of the immune response, although not within the context of MS. They are exploring how the immune attack in different models of EAE may lead to nerve tissue damage in different pathways, depending upon the involvement of immune T cells or B cells, and which pathway leads to progressive MS.
Dr. Kocsis is tackling tissue repair by transplanting bone marrow-derived stem cells into mice with EAE to determine if myelin damage can be repaired and the disease course altered. Cells will be “harvested” from bone marrow in collaboration with Diane S. Krause, MD, PhD, an expert in bone marrow cell biology.
A method of protecting axons is being investigated as well, involving sodium channels – tiny pores along axons that are essential for maintaining proper nerve impulse conduction. Stephen G. Waxman, MD, PhD, winner of the National MS Society/ American Academy of Neurology’s 2002 John Dystel Prize for MS Research, has shown that a drug that blocks sodium channels reduces axonal damage in a type of EAE. He is now extending these studies to other MS models.
Another method of nerve tissue protection is being investigated by team member Richard Flavell, PhD, a noted expert in autoimmunity who recently showed that the immune messenger protein TGF-beta plays a role in controlling autoimmune disease by inhibiting T cells. He is helping explore how TGF-? may regulate EAE and possibly prevent nerve tissue damage. Combining established MS investigators and superb scientists from other fields will provide new approaches and expertise to help translate this basic research into treatment strategies for people with MS.
Region: Minnesota Chapter
Purpose: To screen small molecules forpotential to define functions of myelinmakingcells, and explore how these andlarger antibodies may stimulate repair.
Although the body repairs some damage to nerve-insulating myelin that occurs in MS, this repair is insufficient. One strategy under study encourages internal “repair” capabilities of immune-system proteins called antibodies. Moses Rodriguez, MD, and colleagues have identified human antibodies that attach to oligodendrocytes (myelin-making cells) and promote myelin repair in mice with MS-like disease.
With funding from this award, Dr. Rodriguez has assembled a team of investigators to explore this exciting opportunity further. The team is also studying the potential of “aptamer” technology. Aptamers are tiny pieces of nucleic acids (“building blocks” that make up DNA) which can attach to molecules based on a lock-and-key fit. The Mayo group is investigating their ability to attach to and affect oligodendrocyte or myelin proteins – targets of the immune attack in MS. Unlike larger molecules, aptamers may serve as diagnostic or therapeutic agents without being mistaken for threats by the immune system.
Dr. Rodriguez is employing the extensive “aptamer libraries” of biochemist James Maher III, PhD, to screen for aptamers that attach to oligodendrocytes or myelin components. He is studying how these aptamers affect human oligodendrocytes in test tubes, and in MS tissue obtained from Claudia Lucchinetti, MD, head of the Society-funded MS Lesion Project. Dr. Lucchinetti’s team has identified four patterns of damage that may exist in MS. If aptamers attach differently to myelin components within each pattern, this may indicate their potential to serve as diagnostic tools that identify MS subtypes. Center collaborator Richard Pagano, PhD, an authority on lipid (fatlike molecules) movement in cells, is helping to investigate how antibodies promote myelin repair. He is examining how antibodies and aptamers affect lipids in oligodendrocytes in test tubes, and whether this affects the development of such cells.
The therapeutic potential of antibodies and aptamers will be tracked in mice with MS-like disease using an imaging technology (developed by Dr. Rodriguez with Society funding) which tracks the movement of myelin-making cells in the body. The team is observing how aptamers and antibodies affect such cells in mice with myelin damage, with the help of Slobodan Macura, PhD, director of Nuclear Magnetic Resonance at Mayo.
MS experts in the team include Allan Bieber, PhD (who is helping to coordinate the MS group), who studies genetic mechanisms that lead to myelin repair; Art Warrington, PhD, an expert in the development of oligodendrocytes; and Charles L. Howe, PhD, who is developing a novel method of studying myelin formation. By gathering the talents of MS researchers and experts in new technologies, this team can fully explore the potential of aptamers and antibodies to advance the care and treatment of people with MS.
Why The Immune System Goes Awry
Better treatments and a cure are the ultimate goals of MS research, and perhaps no branch of investigation has borne more fruit toward these goals than the study of the immune system. Current therapies for MS emerged from our growing understanding of how the immune system works and how it can be manipulated to suppress or regulate immune attacks. Several of the newly approved projects listed below are exploring potentially therapeutic compounds in rodent models of MS-like disease; these compounds may someday be developed into medications for people with MS.
Complex interactions can spur on or suppress the immune attack. Researchers also are tracking these interactions to look for clues to further diagnostic or therapeutic strategies.
The National MS Society has current, multi-year commitments of nearly $34.8 million to support 119 research projects focusing on immunology, including 8 new awards.
Region: Wisconsin Chapter
Award: Research Grant
Term/Amount: 4/1/04-3/31/07; $413,576
“Modulation of microglia by minocyclinein CNS disease”
Can an antibiotic inhibit immune activity and protect nerve cells in MS-like disease, and does it have promise for treating MS?
Ian Duncan, PhD, and colleagues have previously shown that the antibiotic minocycline can block the development of EAE – an MSlike disease – in rats, or prevent its worsening when given after disease onset. Now his team is exploring how an antibiotic which usually helps the body fight infection may work against EAE, as a step toward determining its potential for treating MS.
Dr. Duncan and colleagues propose that minocycline may be capable of fighting inflammation by blocking the production of cytokines (immune messenger proteins) by brain cells known as microglia – one of the early events in MS. Blocking the inflammatory activity of microglia may help to protect the nervous system from damage.
The team is focusing on the ability of oral and injected minocycline to block the activation of microglia in mice with EAE at various stages of the disease, and studying its effects on symptoms and on nervous system tissues. This study may yield a new strategy using a widely known antibiotic to treat MS, and possibly to prevent disease progression.
Region: Greater Illinois Chapter
Award: Research Grant
Term/Amount: 4/1/04-3/31/07; $360,113
“Therapeutic potential of PPAR delta agonists in demyelinating disease”
Determining whether a natural brain chemical can stop MS-like disease and stimulate myelin repair by replacement cells.
MS is thought to result from an immune attack on nerve-insulating myelin and nerve fibers, with immune cells migrating into the brain. Recent evidence suggests that medications approved by the FDA to treat diabetes, known as PPAR-gamma agonists, reduce the activity of genes that regulate such immune responses in the brain.
Douglas Feinstein, PhD, found that treatment with PPAR-gamma agonists reduced the incidence and the severity of EAE, an MS-like disease, in mice by blocking immune T cells. His team also has shown that treatment with a slightly different drug – a PPAR-delta agonist – results in the growth and development of myelin-making cells. Together, these two agonists might control immune responses early in disease, and stimulate myelin repair later on.
Dr. Feinstein is exploring the mechanisms by which PPAR-delta can stimulate myelin growth, focusing on the effects of this agent on mice with EAE and in laboratory experiments using isolated mouse and human nervous system cells. This project should provide information on whether PPAR-delta agonist can be a useful treatment for MS.
Region: Greater Illinois Chapter
Award: Research Grant
Term/Amount: 4/1/04-3/31/08; $593,965
“Understanding the role of gamma/delta T cells in relapsing EAE”
The potential of specific immune cells for turning off the immune attack in MS-like disease, and their promise for treating human MS.
In MS, the immune attack against brain and spinal cord tissues is launched by specific immune “T cells.” A different type of T cell – a “gamma/delta T cell” – may be able to regulate and dampen this autoimmune attack by controlling aggressive T-cell responses.
Finding a way to ramp up that control may be a fruitful avenue for trying to prevent the onset, and relapses, of MS. Laurence M. Howard, PhD, is investigating the role of gamma/delta T cells in regulating aggressive T cells that direct the damage in MS. His team is examining how disease-causing T cells develop and function during the course of MS-like disease in mice.
The team is exploring the attack both in the presence and in the absence of gamma/delta T cells. They also are seeking clues to the exact mechanisms by which gamma/delta T cells function and how they communicate and switch off destructive T cells.
This study explores a strategy for using gamma/delta T cells to prevent destructive T cells from causing damage in MS. It may yield a new approach to stopping the disease.
Region: Gateway Area Chapter
Award: Research Grant
Term/Amount: 4/1/04-3/31/07; $523,529
“Chemokines & lymphocyte trafficking in the pathogenesis of experimental autoimmune encephalomyelitis”
Exploring chemical factors that attract destructive immune forces into the brain in MS-like disease, for clues to stopping entry to treat MS.
MS occurs when the immune system directs an attack against nerve-insulating myelin in the brain and spinal cord; nerve fibers are also damaged. Increased numbers of immune cells that react to myelin have been identified both in the blood and in areas of tissue damage in people with MS. Molecules called “chemokines” help immune cells to move into the brain and spinal cord, but the exact chemokines responsible are unknown.
Robyn S. Klein, MD, PhD, is examining the role of chemokines in the development of disease in EAE, an MS-like disease, in mice. Her team is using mice in which the “docking sites” for certain kinds of chemokines have been deleted from the surface of immune cells, preventing these chemokines from being involved in the disease process. The investigators can then examine the effect of loss of specific chemokines on the movement of myelin-directed immune cells into the brain and spinal cord, and on the ability of these cells to induce disease.
Studying the role of chemokines in the development of EAE may provide novel insight into a therapeutic strategy for MS.
“Physician-scientists” are singular members of the scientific community, performing both basic laboratory and patientoriented research. Robyn S. Klein, MD, PhD (Washington University School of Medicine in St. Louis) is one such scientist, and is funded by the National MS Society to apply her talents to MS research. Dr. Klein earned her doctorates in medicine and neuroscience at the Albert Einstein College of Medicine, New York, and then trained in infectious disease and basic immunology at Harvard University, Boston.
This background in neuroscience, immunology, and medicine have primed her for research on MS, in which people’s symptoms are caused by an immune attack on the central nervous system (CNS, the brain and spinal cord).
“I’ve focused on two components of inflammation in the CNS – how immune cells are recruited into the CNS, and how immune system components affect nerve cells,” she says. “Chemokines [immune messenger proteins] play a role in both of these aspects of the attack in MS.”
While at Harvard, Dr. Klein discovered docking sites for chemokines on nerve cells, and that these sites are crucial to how nerve cells proliferate and migrate. Now she is examining how chemokines affect EAE, an MS-like disease, in mice, to better understand how to limit their destructive role in people with MS.
“Understanding how chemokines help to recruit immune cells and damage nerve cells is crucial for developing therapies that limit damage in MS,” says Dr. Klein. Read more about her project above.
Region: Ohio Buckeye Chapter
Award: Research Grant
Term/Amount: 4/1/04-3/31/07; $479,190
“Longitudinal immune- and neurotrophiccytokine responses in MS”
Correlating activity of immune cells with clinical and MRI measures of MS and its progression.
MS is thought to occur when the immune system mistakenly attacks nerve-insulating myelin. Although immune T cells that recognize and launch an attack against myelin proteins have been widely studied in MS, little is known about how their responses change over time and how they correlate with disease activity. A team led by Clara M. Pelfrey, PhD, is tracking how myelin-specific immune responses in MS – specifically, cytokines (immune messenger proteins) – are linked with disability and progression.
Dr. Pelfrey’s team is using new advances in molecular monitoring to track cytokine responses in blood samples from people with MS. The team is examining cytokines that stimulate the immune attack and also “neurotrophic” cytokines, or growth factors, that play a role in nervous system repair and regeneration. They are comparing results from people with relapsing-remitting MS and secondary-progressive MS. Dr. Pelfrey believes that such immune messengers and growth factors may show different patterns and functions, depending upon a person’s symptoms and disease course. These important molecules may thus provide markers for disease activity and progression, and might be developed for treatment purposes as well.
Monitoring changes in immune cells during the course of MS may promote the development of therapies tailored to each stage.
Region: Silicon Valley Chapter
Award: Research Grant
Term/Amount: 4/1/04-3/31/07; $579,374
“Targeting allergy pathways in MS/EAE”
Exploring whether and how antihistamine drugs inhibit MS-like disease and the implications for treating multiple sclerosis.
Research indicates that the immune attack on brain and spinal cord tissues in MS is mediated by immune cells known as T helper 1 (Th1) cells. With this knowledge, investigators have been trying to develop therapies that can “shift” the immune response from employing the inflammatory Th1 cells, to a response that employs their suppressive counterparts, Th2 cells. Lawrence G. Steinman MD, and colleagues, however, have shown that the shift to Th2 can stimulate a dramatic allergic reaction, and in mice, can bring on the MS-like disease, EAE. They are now exploring whether an allergic reaction against the nervous system occurs in MS.
Dr. Steinman’s team recently performed a large-scale analysis of genes in brain lesions – the myelin-damaged areas – from people with MS. Such analyses can point to enzymes, proteins, and other molecules in MS lesions that might be related to the disease cause and severity. They found increased levels of several molecules related to allergy, including “histamine receptor 1” and “platelet activating factor receptor.” They are now exploring whether they can reverse or slow EAE in mice using compounds which inhibit these molecules, such as antihistamines and platelet blockers. They are focusing on the development and severity of disease in the mice, and the impact of such compounds on the immune attack that underlies MS.
This study may provide information on the immune attack in MS which is crucial to the development of new therapies that target this attack.
Region: Oregon Chapter
Award: Research Grant
Term/Amount: 4/1/04-3/31/07; $542,398
“Epitope specific regulation of EAE with recombinant TCR ligands”
Developing a highly targeted experimental therapy that aims at inhibiting only those immune T cells involved in MS attacks.
The immune attack on brain and spinal cord tissues in MS is thought to be launched by T cells that are directed at protein components, or epitopes, of the myelin sheath that insulates nerve fibers. T cells are thought to be activated in MS when a docking protein on the T cell, called the T-cell receptor (TCR), mistakenly binds to myelin components. Arthur Vandenbark, PhD, and colleagues have been attempting to create treatments for MS based on blocking interactions between T cell and myelin, and in this project they are seeking to determine the most relevant players involved and how they function.
The team has developed molecules called recombinant TCR ligands (RTLs), which are designed to bind directly to the receptor on myelin-specific T cells, inhibiting their ability to bind to and cause damage to myelin. Dr. Vandenbark’s team is testing the ability of varying forms of RTLs in altering the activity of T cells from individuals with MS, and also in mice with the MS-like disease, EAE. They are investigating how RTLs alter the signals that alert T cells to attack, and whether they then encourage these cells to prevent other immune cells from attacking.
The team hopes to optimize this approach as a possible treatment for MS. Determining the mechanisms of RTL inhibition can provide the foundation for future clinical trials.
Region: Lone Star Chapter
Award: Research Grant
Term/Amount: 4/1/04-3/31/08; $663,661
“T cell recognition of peptide-MHC conformers in murine EAE”
Exploring factors involved when immune T cells become activated against brain and spinal cord tissues in MS, and ways to intervene.
A key feature of the immune system is the ability of immune T cells to distinguish between normal proteins in the body and those on the surface of invading viruses or bacteria, using self-recognition molecules called HLA. In MS, T cells fail to recognize that the nerve-insulating myelin is part of the body, and they launch attacks against myelin components as if they were invaders. The configuration of HLA coupled with myelin components may be key to this recognition.
E. Sally Ward, PhD, is studying T cells in mice with EAE, an MS-like disease. These cells have “receptors,” molecules on their surface that serve as binding sites for myelin/ HLA molecules that appear to be the target of disease. Her team recently found that the portion of myelin/HLA targeted by T cells in EAE can exist in two distinct molecular shapes, and they are investigating how shape differences may affect T cell responses. Dr. Ward is synthesizing T cell receptors and proteins to analyze their interactions in detail in both test tubes and in mice. The team has developed new ways of tracking T cells as they bind to target proteins in mice.
Investigating how T cells become activated can help to understand their role in the immune attack in MS, and how to stop it.
How Do Nerves Work?
Nerve conduction occurs as a result of the opening and closing of specialized pores or channels, which allow sodium and potassium ions, among others, to flow in and out of the nerve fiber. Researchers are seeking to understand how normal nerve conduction occurs and is regulated – neurophysiology – and the changes in this process seen in MS. Their goal is to find ways to return nerve conduction to its former, healthy state. The National MS Society is currently spending $2.9 million to fund 6 research projects in neurophysiology, including the following two new grants.
Region: Michigan Chapter
Award: Research Grant
Term/Amount: 4/1/04-3/31/07; $566,257
“Molecular control of sodium channel density and localization in myelinated axons”
Investigating how protein pores in nerve fibers become properly clustered to allow for normal nerve signal conduction.
Many people with MS experience symptomfree remission periods, in which nerve fibers conduct nerve impulses even though nerveinsulating myelin has been damaged. Some evidence suggests that this recovery of function is attributable to the redistribution of sodium channels into myelin-damaged areas.
Sodium channels are tiny pores organized in clusters along the nerve fiber that allow it to transmit nerve impulse. After myelin is injured, channels increase in number and move into myelin-damaged areas, temporarily restoring transmission.
Lori L. Isom, PhD, is exploring how two “subunits,” or parts, of sodium channels are involved in controlling their activity. By turning on or off genes that control these subunits in mice, her team has shown that they play important roles in controlling sodium channel number and location, and are required for normal nerve impulse conduction.
Now, Dr. Isom is comparing how these subunits regulate sodium channel function in mice with and without an MS-like disease. This study could lead to a novel therapy that promotes recovery of nerve-signal transmission after myelin damage in MS.
Region: San Diego Area Chapter
Award: Research Grant
Term/Amount: 4/1/04-3/31/07; $419,918
“Formation and maintenance of paranodal axoglial junctions in myelinated nerve”
Studying molecular interactions between nerve fibers and myelin which are crucial to the health of both and which may be future targets for MS therapy.
The myelin sheath that encircles nerve fibers and enables rapid nerve impulse conduction is repeatedly damaged in MS. Recent research indicates that an early event that occurs in myelin damage is the loss of the attachment between myelin and the nerve fiber, which are normally tightly connected at a site called the “axoglial junction.”
Barbara Ranscht, PhD, previously discovered that, during the development of the nervous system, the formation of the axoglial junction is helped when a molecule called Contactin joins with a protein called Caspr.
Now, her team is determining the exact molecular interactions between Contactin and Caspr which are required to form the axoglial junction in myelin-making cells and nerve cells isolated in the laboratory. They are also testing how these interactions are potentially altered in a mouse model of MS. Understanding important molecular interactions that maintain the health of nerve tissues may lead to the design of therapies that prevent myelin damage in MS and facilitate its repair.
Copyright © 2004, National Multiple Sclerosis Society