ms 101175 res sum 2006 eng

MultipleSclerosis

Society of Canada

MS ResearchSummaries 2006

In April, the MS Society of Canadaapproved more than $4.5 million tofund 13 research projects and a record-breaking number of researchscholarships to attract young scientiststo the MS field.

More than $2.6 million was awarded for13 research projects, $300,000 for Dr.Donald Paty Career DevelopmentAwards, $594,500 for postdoctoralfellowships and $786,666 forstudentships.

“The research projects include the bestin basic laboratory research that aretargeted at finding ways to repair thedamage in the brain and spinal cordthat MS causes and in stopping MS

attacks,” said Dr. William J. McIlroy,national medical advisor.

“I am particularly pleased that we arefunding more than 60 researchscholarships. These awards aredesigned to both attract and then keepyoung researchers working to end MS.Our scholarship program has more thandoubled in less than 10 years,” headded.

To be funded, the research projects andscholarships must meet two criticalprinciples. The first is scientificexcellence; they must be the very bestof the research projects and scholarshipapplicants. Second, and equallyimportant, they must be of directrelevance to MS. Both principles mustbe met before they are recommendedfor funding.

Following an exacting review process,the recommended research projects andscholarships go to the Medical AdvisoryCommittee for a definitive overview.The final step is for the NationalExecutive Committee to receive therecommendations and approve thembased on the Society’s availableresources.

The MS Society and the related MSScientific Research Foundation are ableto continue this level of fundingcommitment thanks to the ongoingsupport of individual donors, corporatepartners and MS Society chapters.

MS Society funds increased numberof research grants and scholarships

CONTENTS

Repairing Myelin & Protecting Nerves 2 Immune System Has Key Role 8Looking at Viruses 17How MS Research is Funded 18MRI: Window into MS 19 Managing MS Better Today 21 Collaboration to Speed Results 23

Remyelination in MS 24 Genetic Susceptibility 24Bone Marrow Transplantation 26Development of MS in Children 26

Programs to Attract New Scientific Talent 28Glossary 32 Index 35

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MS Society of Canada - MS Research Summaries 2006

Repairing Myelin andProtecting Nerves

The body uses myelinto cut down on theamount of space andenergy it needs totransmit nerve signals.Without this essentialprotein, the humanspinal cord would needto be several metres

wide and would rack up an unpayableenergy bill to do its job. The body usesmyelin by wrapping it around nervefibres (axons) to form a compact ‘myelinsheath’. In MS, the myelin sheath isdamaged and the cells making myelincan’t repair it fast enough. Not only dothe myelin-stripped axons have difficultysending nerve impulses, but the axonsthemselves are also often damagedbeyond repair. As the damaged myelinheals, scar tissue builds up and formsthe characteristic plaques seen in MS.

All MS research has a converging aim,that is, to prevent or at least minimizethe destruction to myelin in the nervoussystem. Scientists are striving tounderstand the big picture of how thespecialized cells in the nervous systemmake the myelin sheath, and themechanics of how it is wrapped aroundnerve axons. A variety of approachesfrom cell culture techniques, to proteinand gene function analyses, to animalmodel studies and clinical trials shouldhelp scientists achieve their goal. As theprocesses of myelination (myelin growth)and remyelination (myelin regrowth) aremapped out in more detail, bettertherapies will be available to counter thefar-reaching effects of myelin damageduring MS.

Guillermina Almazan, PhD, andWalter Mushynski, PhDMcGill University$305,200 (April 1, 2006 – March 31, 2009)

Role of p38 MAPK (mitogenactivated protein kinase) signallingpathways in myelination

Myelin is made as a membrane extensionof Schwann cells in the peripheralnervous system and of oligodendrocytecells in the central nervous system. Thedominant feature of MS is the formationof large lesions where myelin isdamaged. The immune system cells thatattack myelin cause inflammation of thebrain tissue, and the irreversible loss ofnerve function that follows often goeshand in hand with axon (nerve fibre)damage. To better understand theinteractions between myelin and nervefibres, it is essential to clearly describethe sequence of events and signals thatlead to normal myelination of nervefibres.

Drs. Almazan and Mushynski arespecifically looking at some of themolecular mechanisms required for theinitiation and maintenance of

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Oligodendrocytes (OLIGO) project their myelin-filled cell membranes, wrapping them aroundnerve axons to form the myelin sheath.

myelination. For their experiments, theyare using mixed cultures of dorsal rootganglion neurons (nerve cells) plus eitherSchwann cells or oligodendrocytes. Theyhave identified p38, a member of theMAPK family, as playing a fundamentalrole in the process of myelination. Thereare different types of p38, and one typecalled p38a controls the production ofcytokine messengers involved ininflammation.

These researchers hope to identify theparticular forms of p38 that mightbecome part of new therapies to treatchronic inflammatory diseases likemultiple sclerosis.

Joan Boggs, PhDHospital for Sick Children ResearchInstitute, University of Toronto$311,744 (April 1, 2005 – March 31, 2008)

Glycosphingolipid signaling domainsand protein-protein associations inoligodendrocyte/myelin membranes

Oligodendrocytes wrap their myelin-filledouter membranes many times aroundnerve fibres (axons) to build up themyelin sheath. The resulting sheath is likethe layers of an onion surrounding thenerve axon at the core. Many differentproteins, fats and glycolipids (fats plus asugar) are part of the myelin sheath. InMS, oligodendrocytes cannot fully repairthe damaged myelin sheath. Clues abouthow to help oligodendrocytes do their jobmore effectively can come from studyingthe function of the proteins andglycolipids within the myelin sheath itself.

Dr. Boggs believes that glycolipids andproteins touching each other in differentlayers of the myelin sheath can transmitsignals affecting the health of both myelinand nerve axons. Building on previous MSSociety funding, she is mimicking thesituation where two myelin-filledmembranes in the sheath touch eachother by adding synthetic membranes

containing glycolipids and proteins tooligodendrocytes. Such an approach willallow her to study the behaviour ofoligodendrocytes, and to dissect thesignals involved in oligodendrocytefunction and communication with nerveaxons.

Dr. Boggs’s research could lead to newtherapeutic methods for stimulatingremyelination by oligodendrocytes and forpreventing nerve axon damage in peoplewith MS.

Peter Braun, PhD, and Michel Gravel, PhD McGill University $261,710 (April 1, 2005 – March 31, 2007)

Biological assembly of myelin: role of CNP

Myelination is a complex series of eventswhere oligodendrocyte cells make myelinand project it from their cell surfaces insail-like structures. The ‘myelin sails’ wraparound nerve fibres (axons) many timesforming a protective sheath whichoptimizes the conduction of nerveimpulses. In MS, the myelin sheath isdamaged and, for some reason,oligodendrocytes can’t fully remyelinatenerve axons. Some of the nerve axons diewhile those remaining seem unable tofunction normally. Drs. Braun and Gravelare exploring the fundamental process ofmyelination in an effort to betterunderstand how healthy myelin is madeand maintained.

Their focus is a protein/regulatoryenzyme called CNP/CNPase that may playan important role during myelination ofnerve axons. In previous studies, theyshowed that nerve axon functiondecreased in animals lacking CNPase.Their recent observations point to a rolefor CNP/CNPase while oligodendrocytesmake the ‘myelin sails’ and maintainnerve axon function. They are continuingto explore the theory that CNP is a multi-

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functional protein capable of bindingmany oligodendrocyte proteins and RNA(ribonucleic acid) to promote myelination.

This research might point to CNP/CNPaseas a future therapeutic target forimproving myelination in people with MS.

Timothy Kennedy, PhD McGill University $266,370 (April 1, 2005 – March 31, 2008)

Netrin function in the development ofaxonal-oligodendroglial interactions

The oligodendrocyte cells that makemyelin in the central nervous system(CNS) are lost during diseases like MS.Understanding more about how theseimportant cells mature and becomefunctional is central to winning the battleagainst MS. To that end, Dr. Kennedy isinvestigating the mechanisms controllingoligodendrocyte maturation and function,with the goal of identifying ways topromote myelin regrowth.

Dr. Kennedy recently reported promisingresults from research funded by the MSSociety. Using animal models, he showedthat a protein called Netrin-1 is achemical repellent that pushes immatureoligodendrocytes toward axons in theembryonic CNS. The receptor for Netrin-1, called DCC, is also required for theprocess to occur. In an exciting find, heshowed that Netrin-1 and DCC are madeby different types of neurons, as well asby mature, functional oligodendrocytes inthe adult CNS. Results from post-mortemstudies of human MS plaques has led Dr.Kennedy to propose that too much netrin-1 in MS lesions may inhibit myelinregrowth by preventing immatureoligodendrocytes from reaching damagedaxons.

If Dr. Kennedy can find ways to interferewith Netrin-1 and DCC in MS lesions, hemay be able to help oligodendrocytesreach stripped axons and begin the repairprocess.

Rashmi Kothary, PhD Ottawa Health Research Institute $273,300 (April 1, 2005 – March 31, 2008)

Integrin signalling pathway and CNSmyelination/remyelination

Effective treatments for MS must not onlystop myelin damage but also stimulateoligodendrocyte cells to make new myelinfor damage nerves. Oligodendrocytesundergo many changes before becomingfully functional and capable of myelinatingaxons. It stands to reason thatunderstanding this process in more detailwill help researchers devise bettertreatments for MS.

With previous MS Society funding, Dr.Kothary attacked the problem of howoligodendrocytes myelinate nerve fibres(axons) by focussing on integrins, whichare proteins that span the cell membraneof oligodendrocytes. Integrins are liketelephone operators who connectincoming and outgoing messagesbetween the oligodendrocyte’s exteriorand interior. This two-way communicationaffects how and when oligodendrocyteswill begin to wrap their myelin-filledmembranes around nerve axons. Dr.Kothary is using transgenic mice thatmake different types of integrin to studymyelin loss and regrowth. He is alsocreating other transgenic mice that havea gene to make ILK, a protein inside theoligodendrocyte that carries the integrinmessage. The ILK-transgenic mice willhelp him study the role of ILK inmyelination.

The long-term goal of this work is tomanipulate integrin in a way that willreduce myelin destruction and promotemyelin regrowth in people with MS.

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Mario Moscarello, PhD Fabrizio Mastronardi, PhD Hospital for Sick Children, Toronto $203,570 (April 1, 2006 – March 31, 2008)

Demyelination and remyelination inMS. The role of Vitamin B12 andmethylation

MS is characterized by loss of myelinsurrounding axons (nerve fibres), andfailure of the stripped axons to beremyelinated by oligodendrocyte cells. Inaddressing these two issues, Drs.Moscarello and Mastronardi found that anenzyme called PAD alters myelin basicprotein, causing myelin destabilization.

In searching for reasons why this mightoccur, they found that the start of thePAD gene had fewer chemical groupscalled ‘methyl groups’ than normal,meaning that more PAD was made. Theyare currently exploring whether vitaminB12 can increase the number of methylgroups at the start of genes. Theycontinue to study molecules such as sonichedgehog, Notch-1 and stathmin. Todate, they have shown that decreases insonic hedgehog and increases in Notch-1and stathmin prevent oligodendrocytematuration. Without matureoligodendrocytes, stripped nerve axonscannot be remyelinated.

In the last period funded by the MSSociety, they found that B12 incombination with beta interferon orpaclitaxel dramatically improved theclinical symptoms in various animalmodels of MS. Given their results, Drs.Moscarello and Mastronardi haverecommended that vitamin B12 be usedin the treatment of people with MS.

Alan Peterson, PhD McGill University $229,020 (April 1, 2004 – March 31, 2006)

Regulation of the oligodendrocytegenome

In people with MS, brain lesions that lackmyelin are often not repaired despite thepresence of oligodendrocytes (myelinmaking cells) that can fix the damage.

Dr. Peterson is looking for a solution tothis problem by investigating themolecules that control myelin formation,maintenance and repair.

Technical advancements during the lastfunding period have enabled the team tobetter focus their efforts on the myelinbasic protein (MBP) gene. They comparedmouse and human genomes and found aregulatory system composed of morethan 1,000 base pair sequences of DNAthat controls the switch for the MBP gene.Curiously, not all parts of the regulatorysystem are used equally in the developingor mature nervous system. For example,the regulatory parts that control myelinregrowth are different from those usedduring nervous system development. Withits renewed funding, the team will use the1,000 base pairs of sequence to captureinteracting proteins that are involved innormal MBP production.

Development of new therapeuticstrategies capable of enhancing myelinstability and repair should becomepossible once the control mechanismsregulating myelin formation, maintenanceand repair are known.

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Christopher Power, MD University of Alberta $240,000 (April 1, 2003 – March 31, 2006)

Purine receptor-mediated immuneregulation in multiple sclerosis

In MS, inflammation of the centralnervous system (CNS) leads to myelinloss, damage to nerve fibres and oftenphysical disability in people who have thedisease. Dr. Power’s approach to theseproblems is to study the adenosine A1receptor, which he recently linked to braininflammation in people with multiplesclerosis.

Adenosine A1 receptors are found onmacrophages in the blood and brain.These receptors bind to adenosine, whichis known to protect against someneurological diseases. In previous work,Dr. Power showed that the levels andfunction of adenosine A1 receptors arelower than normal in people with MS. Inthe present study, he is focusing on howthe damage in MS is linked to havingfewer adenosine A1 receptors. He is usingmice lacking the adenosine A1 receptor,and blood and brain tissue of people withMS to see if the damage in MS is linkedto fewer adenosine A1 receptors.

This research may lead to new therapiesthat would harness the protective effectsof adenosine A1 receptors. Such therapiescould ultimately decrease the damagefrom inflammation of the CNS in peoplewith multiple sclerosis.

Stéphane Richard, PhD Lady Davis Research Institute,Jewish General Hospital, Montreal $295,830 (April 1, 2006 – March 31, 2009)

The role of quaking proteins inoligodendrocyte physiology andmyelination

One unusually named animal model of MSis the ‘quaking viable mouse’. It gets its

name from the tremors that occur shortlyafter birth in mice with defective quakingproteins. Dr. Richard’s lab has shownthat mice lacking the quaking proteinsalso have myelin defects. He continuesto study the function of quaking proteinsin an effort to tease out how they arerequired for the growth of myelin-makingoligodendrocyte cells.

Dr. Richard has made considerableprogress since his previous grant fundedby the MS Society. He has published twomajor research papers on quakingproteins and has another manuscript inpreparation. In one of the researchpublications, he presented unique datashowing that quaking proteins 6 and 7can cause oligodendrocyte differentiationand maturation. These oligodendrocytescan come from parent cells (neuralprecursors) in the brain, and also fromimmature oligodendrocytes in cellcultures.

With the renewed research grant, Dr.Richard is continuing to study the potentialof quaking proteins to causeoligodendrocyte growth. In the future, hisstudies may provide a way to repair myelinby using therapies that enhance thefunction of quaking proteins 6 and 7.

Peter Stys, MD University of Ottawa $165,668 (April 1, 2006 – March 31, 2008)

Mechanisms of axon spheroidformation

MS is an autoimmune disease where thebody’s own immune system mistakenlyattacks the brain tissue. The brain ismade up of ‘wires’ called axons that areinsulated with a material called myelin.Axons play the critical role of transmittingelectrical impulses within the nervoussystem. When attacked by the immunesystem, myelin is damaged and the wire-like axons are cut. The severed axonsmight be the most important feature of

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MS, because once cut, they degenerateand disappear forever from the brain andspinal cord. After enough axons are lost,the brain suffers permanent andprogressive loss of function.

Before damaged axons are severed, theyswell up in a process called spheroidformation. Although this phenomenon hasbeen observed microscopically for over150 years, there is still no clear idea whatcauses the swelling. Dr. Stys’ researchteam has developed a tissue modelmimicking axon swelling so he canvisualize the process in real time withlaser scanning microscopes.

Using this unique process, Dr. Stys hopesto learn more about what triggers axonswelling, and the drugs that might beused to prevent it in people with MS.

Valerie Anne Wallace, PhD Ottawa Health Research Institute $74,746 (April 1, 2004 – March 31, 2006)

With additional funding from theCanadian Institutes of Health Research

The role of neuron-derivedmorphogens in optic nervedevelopment

A major goal in the treatment of MS is topromote the addition of new myelin(remyelination) to damaged regions ofthe central nervous system. In themajority of MS cases, this vital repairprocess is incomplete, and to date notherapy fully restores the damage. Thereis growing evidence that morphogens(growth stimulators) may link the cell-to-cell communications that contribute toeffective remyelination of damagednerves.

Dr. Wallace is studying the communicationbetween nerve axons and astrocytes(support cells) in the developing rodentoptic nerve. Messages from nerve axonspromote astrocyte development, and Dr.Wallace is the first to show that a

morphogen called Sonic hedgehog is thesignal go-between. How Sonic hedgehogdoes this is important because astrocytesare key to the remyelination process.They make messenger proteins involvedin the development of oligodendrocytes,the cells that make and maintain myelin.Garbled communication from astrocytesmay be one of the reasons that nerveaxons are not well remyelinated. Dr.Wallace’s long-term goal is to discoverthe details of how Sonic hedgehog works,what its targets are and how it getstransported in neurons.

By learning more about how morphogenscontribute to nerve, astrocyte andoligodendrocyte communication, newways to promote nerve remyelinationafter injury due to MS may becomeapparent.

V. Wee Yong, PhD University of Calgary $352,500 (April 1, 2004 - March 31, 2007)

Beneficial roles of matrix metallo-proteinases (MMPs) in myelinformation

The myelin sheath is created from thelong, slender myelin-filled membranesthat radiate from oligodendrocytes. If thisvital process could be enhanced andoligodendrocyte survival ensured, myelinloss might be stopped or slowed duringMS. To this end, Dr. Yong is searching forways to promote the very survival and

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The key principles guiding theMS Society research programare: excellence and relevanceto MS. The MS Society willsupport only the best researchprojects and the best youngscientists.

function of oligodendrocytes by focusingon matrix metalloproteinases (MMPs).MMPs are well positioned to promotemyelin regrowth as they helpoligodendrocytes develop and extendtheir myelin-filled membranes aroundnerve fibres.

In research previously funded by the MSSociety, Dr. Yong found that astrocytes(support cells in the brain) interactdirectly with surface proteins onoligodendrocytes, sending them signalsthat enhance their survival. He alsoshowed that MMP-9 is made at the site ofbrain tissue injury during myelinregeneration in mice, and that MMP-12levels are increased in humanoligodendrocytes extending theirprocesses. In some mice, the loss ofMMP-9 and MMP-12 impairs myelinformation. He is continuing to study theneed for MMP-9 and MMP-12 in myelinformation. Some MS therapies aredesigned to inhibit certain MMPs whichhelp inflammation-causing white bloodcells to enter the brain. Dr. Yong willassess whether chronic inhibition of MMPactivity by such therapies actually impairsmyelin formation in the long-term.

This study may lead to new therapiesbased on MMPs which would help restorethe myelin sheath and promote recoveryin people with MS.

Immune System Has Key Role

Cells of the immunesystem are constantlybattling to defend thebody against invadingviruses, bacteria andother threats. Since theimmune systemnormally protects the

body from such dangers, it is puzzlingthat it should turn its deadly arsenalagainst myelin and the cells that make itduring MS. Some scientists believe thatinfectious agents can act as catalysts to“trigger” the immune system attack insusceptible individuals. The term“autoimmunity” has been coined todescribe how the immune systemunwittingly attacks the body in the sameway that it fights off an infection.

Although scientists are making constantheadway, there is still a long way to gobefore they fully understand the immunesystem attack during MS. Much of theresearch effort focuses on determiningthe role of white blood cells (T cells, Bcells, macrophages, mast cells, etc.)during inflammation in MS, anddiscovering how the tight seal of theblood-brain-barrier (BBB) loosens to allowwhite blood cells into the brain. Equallyimportant are studies evaluating new andexisting immunotherapies that can helpclinicians to tailor treatments for peoplewith different forms of MS. As more andmore pieces of the immunological puzzlesurrounding MS are discovered,researchers will be able to design newtreatments aimed at bringing the immunesystem back onside.

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Jack Antel, MD Montreal Neurological Institute, McGill University $306,000 (April 1, 2004 – March 31, 2007)

The systemic immune response in multiple sclerosis and effects of therapy

The initial lesions in MS are caused byimmune cells called lymphocytes thatleave the blood vessels and cross theblood-brain-barrier (BBB). This barrier ismade of lines of endothelial cells thatnormally prevent lymphocytes fromsqueezing into the brain tissue. Dr. Antelhas developed an artificial model of theBBB to study how dangerous lymphocytesmanage to breach the tight seal of theBBB.

During the previous granting period, Dr.Antel used his artificial model to showthat immune cells called microglia makefactors that enhance the tight seal of theBBB. He also showed that lymphocytesfrom people with active MS can cross theartificial BBB faster than lymphocytesfrom people with stable MS. His currentwork revolves around how interactionsbetween lymphocytes and BBBendothelial cells alter each of these celltypes and set the stage for theprogression of MS. Dr. Antel is alsocontinuing his studies on beta interferonand its ability to alter T cells which inturn might have positive or negativeeffects on BBB endothelial cells.

These studies will get directly at thequestion of how lymphocytes cross theBBB. In the future, Dr. Antel’s results mayhelp identify particular aspects oflymphocyte-endothelial cell interactionsthat could serve as new therapeutictargets for people with MS.

Jack Antel, MD and Amit Bar-Or, MDMontreal Neurological Institute,McGill University $180,000 (April 1, 2004 – March 31, 2006)

Microglia as regulators and effectorsof the immune response in thecentral nervous system

MS most often follows an initial relapsing-remitting course and then evolves into amore progressive phase. Drs. Antel andBar-Or think that front-line immune cellscalled microglia and monocytes arecentral to each phase of the disease.Microglia are cells that reside in the brainand are a first line of defence againstinvaders. Monocytes migrate from theblood to the brain and are found in activeMS lesions. Both cells ‘eat’ cellular debrisand stimulate immune responses. Drs.Antel and Bar-Or think that microglia andmonocytes contribute to tissue injury andrepair in the brain during MS.

To tackle their research, they are takingadvantage of access to human adultcentral nervous system tissue as a sourceof microglia. They are using peripheralblood from volunteers and people withMS, including those receiving disease-modifying therapies, as the source ofmonocytes and other immune cellsrelevant to MS. The researchers havedeveloped MS-like conditions in cellcultures to test a variety of processesimplicated in disease progression. First ontheir list is to determine how signals fromimmune cells, oligodendrocytes (myelin-making cells) and myelin impact onmicroglia and monocytes. Then they willcheck how receptors found on microgliaand monocytes direct microglia andmonocyte responses.

These studies should enhance theunderstanding of MS and suggesttherapies which downplay the pro-injuryactions and encourage the repair actionsof microglia and monocytes.

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Amit Bar-Or, MD Montreal Neurological Institute, McGill University $44,679 (April 1, 2003 – March 31, 2006)

With additional funding from theCanadian Institutes of Health Research

Human B cell subsets: Immuneregulatory properties and role inmultiple sclerosis

Most MS research to date has focused onhow immune system T cells cause tissuedamage in the central nervous system. Itis becoming clear that another type ofimmune cell, the B cell, may also beinvolved. B cells normally protect thebody by making antibodies to fightinfections. For some reason, B cells canalso cause considerable damage forcertain people with MS.

Dr. Bar-Or recently identified a particulartype of memory (long-lived) B cell thatcan trigger T cells and make anabundance of antibodies. He finds highlevels of these memory B cells in peoplewith progressive MS. Samples collectedfrom blood and cerebral spinal fluid (CSF)in people with and without MS will helphim to narrow down who is most likely tohave the memory B cells. He is alsotesting if the memory B cells can makeantibodies against myelin and how theymight be triggering T cells. Anotherimportant question to address is howeasy it is for the memory B cells to crossthe blood-brain-barrier.

Dr. Bar-Or’s study will help form thefoundation for new therapies specificallytailored for people who are most likely todevelop these destructive memory Bcells.

Samuel David, PhD McGill University $239,921 (April 1, 2004 – March 31, 2007)

Pathogenesis and treatment ofchronic experimental autoimmuneencephalomyelitis

MS in an inflammatory disease of thecentral nervous system (CNS) that canresult in myelin loss, sensory loss andeven paralysis. The clinical course of MSvaries from person to person and includesrelapsing-remitting and chronic(progressive) forms. Although a variety offactors likely trigger MS in susceptibleindividuals, those that promoteinflammation and damage to myelin aregood candidates to study. For this reason,Dr. David is focusing on the enzyme PLA2

whose by-products can dissolve myelinand cause inflammation.

Dr. David’s studies take place in mice thatdevelop an MS-like disease calledexperimental autoimmuneencephalomyelitis (EAE). In previousresearch funded by the MS Society, heshowed that PLA2 is expressed at highlevels in spinal cord lesions in therelapsing-remitting form of EAE. He alsofound that chemical inhibitors of PLA2 cansignificantly reduce the onset andprogression of relapsing-remitting EAE.With continued funding from the MSSociety, he plans to broaden his studies toinclude a mouse model of chronic EAE.The changes in inflammation and nervedamage in the spinal cord at variousstages of chronic EAE will be studied, aswill the role of PLA2.

Studying EAE mice will give researchersmore clues about how to designtreatments, such as PLA2 inhibitors, thatmight block inflammation and CNSdamage in people with various forms ofmultiple sclerosis.

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Samuel David, PhD McGill University $84,186 (April 1, 2006 – March 31, 2008)

Selective roles for different membersof the phospholipase A2 family in EAE

Experimental autoimmuneencephalomyelitis (EAE) is a widely usedanimal model of MS. Dr. David has shownthat an enzyme called phospholipase A2(PLA2) plays an important role in the onsetand progression of EAE in mice. He hasidentified an inhibitor compound thatblocks PLA2 and reduces the onset andprogression of EAE. However, there areseveral different types of PLA2, some ofwhich have normal functions in the body.Unfortunately, the inhibitor compoundblocks those forms of PLA2 as well.

Dr. David now has evidence that four out offourteen PLA2 tested are increased in thespinal cord and spleen of EAE mice. Hispreliminary data show that these four PLA2

may be involved in different phases of EAE.He is collaborating with a scientist inGreece who has developed specificinhibitors for the four PLA2 enzymes. Thegoal of the current proposal is to find outwhich cells in EAE lesions produce the fourdifferent forms of PLA2, and to assess theirrole by selectively blocking them with thespecific inhibitors.

If successful, this novel group of inhibitorscould be further developed and tested forthe treatment of MS in humans.

Katerina Dorovini-Zis, MD Vancouver General Hospital $292,890 (April 1, 2006 – March 31, 2009)

Human cerebral endothelium-lymphocyte interactions in immune-mediated CNS diseases

During MS, the blood-brain-barrier (BBB)becomes leaky and destructive immunesystem cells enter the brain. Endothelialcells (ECs) line all the blood vessels in thebody, including those of the BBB. ECslining the BBB of the brain are the firstcells to meet circulating immune system

cells. Because of that, Dr. Dorovini-Zispredicts that the interactions betweenthese cell types are likely important for thebrain damage seen in MS.

Dr. Dorovini-Zis has made considerableprogress since the last granting termfunded by the MS Society. She haspublished seven research papers, andcurrently has several other manuscripts inpreparation. These papers explore the roleof ECs in stimulating immune system cellsto cross the BBB. With these details firmlyin hand, Dr. Dorovini-Zis pushes forward tostudy whether the immune system T cell(which enters the brain to damage myelin)is activated by ECs at the BBB. Theartificial model of the BBB pioneered in herlab is still the major tool she uses toobserve the EC-immune system cellinteractions under closely controlledconditions.

This research may point to specifictherapies targeted at restoring the normalfunction of ECs lining the BBB in peoplewith MS.

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T cells and monocytes (MONO) enter the braintissue by squeezing through endothelial cells thatline the blood brain barrier.

Alexander Easton, MBBS, PhD Chunahi Hao, MD, PhD Dalhousie University $129,343 (April 1, 2006 – March 31, 2008)

Inflammatory modulation of theblood-brain barrier by Fas ligand andTRAIL

During MS, myelin is attacked byactivated T cells, immune system cellsthat ordinarily protect the body. ActivatedT cells do not normally reside in thebrain. For them to damage myelin, theymust first leave the blood and enter thebrain tissue by interacting withendothelial cells lining the blood vesselsof the brain. Brain endothelial cellscreate a blood-brain-barrier (BBB) whichrestricts the entry of cells and substancesfrom the blood into the brain. During theinflammatory process that occurs in MS,the tight seal of the BBB is broken. Thisprocess occurs in part because of theactivity of cellular messengers calledcytokines, particularly tumor necrosisfactor (TNF).

Drs. Easton and Hao are studying twomembers of the TNF family, called Fasligand and TRAIL. Their role inendothelial cell activation is unclear, butthe researchers have discovered alreadythat Fas ligand promotes the activation ofbrain endothelial cells while TRAIL inhibitsit. In cell culture models of the BBB, Fasligand increases T lymphocyte adhesionand permeability, while TRAIL reducespermeability without promoting adhesion.This means that Fas ligand might increasethe movement of T cells across the BBB,while TRAIL might reduce it.

With the new operating grant, theresearchers hope to confirm their initialfindings and explore the various signalsinvolved. If TRAIL reduces inflammation,it may have an exciting therapeuticpotential in MS.

Alyson Fournier, PhD, and Amit Bar-Or, MD McGill University $219,740 (April 1, 2005 – March 31, 2007)

Myelin inhibitory molecules and theneuro-immune interface

The influx of activated immune systemcells across the endothelial cells lining theblood- brain-barrier (BBB), myelin lossand nerve fibre (axonal) injury are allhallmarks of MS. Axonal injury is nowrecognized as the major instigator ofsustained neurological disability. Drs.Fournier and Bar-Or’s research focus is tostudy the mechanisms that limit axonregeneration.

When the myelin sheath is damagedduring MS, several myelin proteins thatare normally embedded in the sheathbecome exposed. These proteins, themost potent of which is called Nogo A,are known to inhibit the ability of axonsto be regenerated. Nogo A binds to theNogo A receptor (NgR) on axons andleads to their collapse. Some studiesshow that blocking Nogo in an EAE animalmodel of MS leads to better axonregeneration and recovery. Dr. Fournierrecently discovered that Nogo A is foundon activated human immune system cells,and that NgR is found on endothelial cellslining the human BBB. The researchersare building on their findings to decipherthe role of Nogo A during the MS diseaseprocess.

Therapies arising from the work on NogoA would be aimed at optimizing axonalrepair and minimizing the accumulation ofdisability in people with MS.

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Sylvie Fournier, PhD McGill University $181,264 (April 1, 2006 – March 31, 2008)

Pathogenic mechanisms in an animalmodel of CD8+ T cell-mediateddemyelinating disease

Multiple sclerosis is an inflammatorydisease of the central nervous system(brain and spinal cord) where immunesystem T cells play an important role.There are two major types of T cells:CD4+ T cells and CD8+ T cells. Over theyears, CD4+ T cells have been held almostexclusively responsible for MS. Recentevidence, however, suggests that CD8+ Tcells may also contribute to starting andcontinuing the disease process. How thesecells might cause inflammation in thenervous system is largely unknown.

Dr. Fournier has generated a new model ofMS in which mice spontaneously develop aneurological disease similar to MS inhumans. She has shown that the MS-likedisease is caused by the activation ofCD8+ T cells in the nervous system.Further study of this animal model shouldallow her to dissect the steps by whichCD8+ cells are triggered, leading toinflammation and injury of the nervoussystem.

Aside from broadening the understandingof MS, this research might also lead to thedevelopment of new therapeuticapproaches to prevent CD8+ T cells fromcausing the nerve damage so devastatingin MS.

Fabrizio Giuliani, MD University of Alberta $172,000 (April 1, 2006– March 31, 2008)

Role of inflammation inneurodegenerative processes ofmultiple sclerosis

MS typically displays a relapsing coursemarked by episodes of neurological

disability. Such episodes are followed byperiods of partial or complete remission.Axon and neuron (nerve cell) damage canlead to permanent disability, and severeaxon (nerve fibre) damage might even beresponsible for turning relapsing-remittingMS to the secondary-progressive form.

The cause of tissue damage in MS isuncertain, but inflammation likely plays arole since axon damage increases asinflammation worsens within a lesion. Dr. Fabrizio has determined that humanneurons are extremely vulnerable to injuryby T cells, immune system cells thatnormally protect the body. He has focusedhis research on learning how T cells andother immune system cells causeinflammation, neuron and axon damage.

Dr. Fabrizio is also exploring new anti-inflammatory combination treatments andtheir potential to reduce inflammation inEAE mice with an MS-like disease. Hisresults are so promising that they haveprompted a Phase II clinical trial on 40people with MS at the University of Calgary.The long-term goal of the trial is to identifynew anti-inflammatory therapies that mightlessen inflammation in MS lesions, and alsoprevent people with MS from transitioningto the progressive phase of the disease.

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MS Research Commitments at a Glance

Total MS Society-funded research projects 37

Total Foundation-funded collaborative projects 4

Total MS Society-funded scholarships 61

Donald Paty Career Development Awards 6

Postdoctoral Fellowships 15

Research Studentships 40

Total Foundation-funded Pilot Research Projects 3

Jennifer Gommerman, PhD University of Toronto $218,039 (April 1, 2005 – March 31, 2007)

Evaluating the role of thelymphotoxin pathway in EAE

Lymphocytes are immune system cellsthat fight infections in our body. DuringMS, the body’s own lymphocytes can alsoattack parts of the central nervoussystem (CNS). Before lymphocytes canattack the CNS, they must first beactivated in the lymph nodes and fromthere migrate to the CNS. Understandingthis process will help researchers todevelop better therapies for treating MS.

Dr. Gommerman believes that an inhibitorof the lymphotoxin pathway might beinvolved in the process, and prove to be agood candidate therapy for MS. Thislymphotoxin pathway is made up ofcytokine messenger molecules and othersignalling molecules that are involved inthe developing and adult immune system.In previous studies, the lymphotoxinpathway inhibitor prevented EAE, an MS-like disease in rodents. However, the EAErodents used did not provide usefulinformation about the lymphocytescausing CNS damage. Dr. Gommerman isusing a new type of EAE mouse that hasbeen genetically altered so that itdevelops both spontaneous and inducedEAE. With this model, she will be able totrack the fate of the CNS-attackinglymphocytes and study the lymphotoxinpathway inhibitors in parallel.

Putting this information together will leadto a better understanding of howlymphotoxin inhibitors prevent EAE, andwhether or not they might havetherapeutic value in people with MS.

David George Haegert, MD, and Veerabhadra Gadag, PhD McGill University $310,956 (April 1, 2005 – March 31, 2008)

Altered naïve T-cell homeostasis inmultiple sclerosis

Immune system T cells are made in thebone marrow and travel to the thymuswhere they mature before being releasedinto the blood. This process is tightlycontrolled in healthy people. Based ontheir recent findings supported byprevious MS Society funding, Drs.Haegert and Gadag are proposing thatpeople with MS have fewer T cells. Lowernumbers of T cells in people with MS mayalso be linked to additional T cellabnormalities.

The scientists have identified a markerthat measures the number of naïve(untriggered) T cells made by thethymus. Drs. Haegert and Gadag aretesting for the marker in people withrelapsing-remitting MS and primary-progressive MS, as well as in people withclinically isolated syndrome (a singledemyelinating event). They are alsostudying factors influencing T cellregulation in these groups.

Showing reduced numbers of T cellsmade by the thymus in people with MSwould be important in three ways. First,an abnormality in T cell production mightprecede the onset of MS, and help explainwhy some individuals develop thedisease. Second, identifying lowernumbers of naïve T cells in people withprecurser lesions (those that resultbecause of a single demyelinating event)might help to predict who will go on todevelop MS. Third, the marker of T cellproduction may identify people withprecursor lesions who need earlytreatment to prevent the development ofclinically definite MS.

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Stephen Karlik, PhD University of Western Ontario $217,956 (April 1, 2005 – March 31, 2007)

Angiogenesis in chronic EAE

Chronic inflammation outside the centralnervous system depends in part onangiogenesis, the process of growing newblood vessels from existing ones. Thenew blood vessels that form are like ahighway along which nutrients andimmune system cells can travel to thetissues causing inflammation which leadsto damage. Angiogenesis is known tocontribute to chronic inflammatorydiseases like rheumatoid arthritis andpsoriasis, but its contribution to MS is stillunknown.

Dr. Karlik recently found thatangiogenesis occurs in the spinal cord ofmice and guinea pigs with EAE, an MS-like disease. Increased levels of VEGF, amolecule that promotes angiogenesis, canbe found in the animals. He also foundthat interfering with HIF-1, a moleculethat controls VEGF, exposes the animalsto high oxygen levels and dramaticallyalters the course of inflammation. Dr.Karlik is examining the role of VEGF byblocking its action with a vaccine or withsafe thalidomide derivatives. He is alsoinvestigating why breathing higheroxygen levels can decrease inflammation.

By studying the connection betweenangiogenesis, VEGF and HIF-1, Dr. Karlikhopes to identify ways to blockangiogenesis in animals with EAE, andprovide new possibilities for treatingpeople with MS.

Paul Kubes, PhD University of Calgary $176,352 (April 1, 2004 – March 31, 2006)

The role of TLR4 and mast cells in the development of CNSautoimmune disease

Why some people develop MS and othersdo not is an unresolved question. Mostresearch focuses on the role that T cellsplay in MS. It is clear however, that Tcells able to attack myelin in people withMS are not the whole story becausehealthy individuals have such T cells aswell. Researchers think thatenvironmental factors, including earlyexposure to some infectious agents, likelyplay a critical role in starting MS. Howthis might happen is still a mystery.

Dr. Kubes has identified the TLR4receptor, which binds invading infectiousagents, as a possible mediator ofenvironmental factors involved in MS.TLR4 is found on many immune cells, butone in particular – the mast cell – is agood candidate for this study. It residesin tissues exposed to the environment,accumulates around MS lesions andmakes factors that lead to inflammationand stimulate immune responses. Dr.Kubes is assessing the role of mast cellTLR4 in an animal model of MS. He alsohopes to discover how and why mast cellsaccumulate in the brain during the courseof MS, and how exactly such cellscontribute to disease development in MS.

This innovative research may show thatmast cells are the interface for theenvironmental influences that initiate MS.If this proves to be correct, mast cellsand mast cell TLR4 might be two newtherapeutic targets for the treatment andprevention of MS.

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Trevor Owens, PhD McGill University $309,480 (April 1, 2005 – March 31, 2008)

Immune-glial interactions in CNS inflammation and demyelinating disease

Inflammation is characteristic of MS and isassociated with the entry of immunesystem cells into the brain. These cellsmainly include T cells, many of which canattack myelin, and macrophages, whichcan contribute to tissue inflammation. Thepoint at which macrophages and T cellsenter the brain marks a pivotal step in thecascade of events that lead to MS.Dissecting the cascade is critical forcontrolling this disease.

In previous MS Society funded research,Dr. Owens showed that damage to nervefibres (axons) in the brain causes residentsupport cells, called glial cells, to makechemokines. These are messengermolecules that attract immune systemcells to the chemokine source. He alsoshowed that Toll-like receptors, whichnormally bind parts of invading organismsin front-line immune responses cancontrol how cytokine messengermolecules respond to injury. Toll-likereceptors are also critical for T cell entryinto the brain. Dr. Owens is usinggenetically modified mice to furtherexplore how Toll-like receptors, cytokinesand chemokines influence macrophageand T cell entry into the brain. He believesthat not all immune system cells enteringthe brain cause damage and wants tolearn how to control the outcome ofmacrophage and T cell entry into thebrain.

Taken together, Dr. Owens’s results shouldcontribute to a better understanding ofMS and help to control the immuneresponse in people with this oftendisabling disease.

Alexandre Prat, MD, PhD Montreal University $295,491 (April 1, 2006 – March 31, 2009)

Origin, regulation and function ofbrain perivascular dendritic cells inMS

The presence of dendritic cells (DCs) inhuman and mouse brains has been acontroversial topic for more than adecade. DCs have the pivotal role oftriggering T cells in the immune system.Several independent investigators havefound that DCs associated with the bloodbrain barrier (BBB) are important for theformation of lesions in EAE, an animalmodel of MS. The BBB is a network ofblood vessels that nourishes the brainand is lined by endothelial cells.

To aid his research, Dr. Prat hasdeveloped a human model of the BBB. In his current proposal, he is investigatingwhether endothelial cells lining the BBBmake cytokine messengers that influencethe development of DCs. Because theseDCs are associated with BBB endothelialcells, Dr. Prat calls them ‘eDCs’. He iscurious whether eDCs can trigger or haltthe activation of different types of T cellsthat might be present in MS lesions. Toconfirm his findings, Dr. Prat will takeadvantage of his substantial bank of MSbrain specimens.

This proposal offers the potential todiscover how eDCs are formed andwhether they sustain or counteract thedamage that T cells cause during MS.

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Luc Vallières, PhD CHUL Research Centre, Quebec City $63,000 (April 1, 2004 – March 31, 2006)

Regulation of cerebral macrophagegenesis in a murine model of multiple sclerosis

Microglia and other brain macrophagesstimulate immune responses within thecentral nervous system. The verdict is stillout, however, as to whether these cellsplay a helpful or harmful role in MS.While these macrophages repair neuraldamage by ‘eating’ cellular debris, theyalso produce soluble messengers thatpromote inflammation which can lead tosecondary tissue damage.

The main goal of this research is todiscover the signals that promote thedevelopment of brain macrophages withthe view of designing more effective anti-inflammatory therapies. Dr. Vallières’sstarting point is to better understand therole of tumor necrosis factor (TNF), asoluble messenger made by macrophagesand other immune cells. Anti-TNF hasrecently been approved for therapeuticuse in rheumatoid arthritis and may beuseful for treating MS as well. However,some studies show that inhibiting TNF canpromote myelin loss. In fact, Dr.Vallières’s work in mice underscores this.He finds that too many microglia formafter nerve axon damage in mice thatlack TNF. Using a mouse model of MS, Dr.Vallières will follow macrophage formationand test whether TNF plays bothinflammatory and suppressive rolesduring immune responses in the brain.

This research may lead to thedevelopment of more selective anti-TNFtreatments aimed at slowing theprogression of multiple sclerosis.

Looking at VirusesThe idea that virusesplay a role inautoimmune diseasessuch as MS is gainingcredibility. Over the past60 years almost 24viruses, including rabies

virus, coronavirus, herpesviruses,measles virus, and retroviruses, havebeen isolated from brain tissue of peoplewith MS. Although a person may beinfected with one of these viruses, he orshe may not necessarily go on to developMS. This observation suggests thatviruses do not cause MS directly but maybe linked to its development insusceptible people.

Scientists are striving to discover theconnection between viruses and MS.Some scientists suspect that virusfragments resemble certain bodyfragments. This theory is called‘molecular mimicry’ and leads to theimmune system mistakenly attacking thebody fragments while it is attacking thevirus. Other scientists believe that virusinfections ramp up dendritic cells of theimmune system that can trigger‘autoreactive’ T cells, which are pre-armed to attack the body for somereason. This theory is called ‘bystanderactivation of autoreactive T cells’. Anothertheory is that ‘persistent viral infections’prolong the immune system attack onvirally infected tissues, resulting ininflammation and tissue damage.

Whatever the scenario, the story is farfrom straightforward because someviruses can also protect people fromoverzealous immune systems that causeinflammation during autoimmunediseases like MS. Future research willtake advantage of many new and existingtechnologies in order to evaluate howone’s history of viral infection combineswith genetics and environmentalinfluences to increase the risk of MS.

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Christopher Power, MD University of Alberta $294,000 (April 1, 2006 – March 31, 2009)

Pathogenic interactions betweenhuman retroelements andneuroinflammation in MS

How viruses affect the immune systemduring MS is still unclear. Interestingly, 5-10% of the human genome is made up ofviruses called ‘retroviruses’. Theseviruses have been incorporated into thehuman genome over millions of years ofevolution. Dr. Power has found that agroup of unique retroviruses are made inthe brains of some people with MS.Moreover, he has found an abundance ofa particular retrovirus gene in the brainsof people with MS. This gene contributesto the activation of the immune systemand damage to myelin in cell cultures andin animal models.

Dr. Power is combining unique microarraytechnology with new transgenic mice andother detection tools to evaluate the levelof different retroviruses in people withMS. The long-term goal of this project isto identify the contribution that suchretroviruses might make to theprogression of MS. He has alsodeveloped a new retrovirus-containingtransgenic mouse which he can use tostudy myelin damage and the effects ofnovel therapies for MS.

Taken together, this research shouldaddress the growing question of the roleof viruses in MS, and also provide newtherapeutic opportunities for itstreatment.

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The MS Societyfunds a largeand respectedMS researchprogram thattotals between$6 and $7million annually.

It provides funding to researcherscarrying out a wide variety ofapproaches to solve the MSproblem and also supports youngscientists with careerdevelopment awards,postdoctoral fellowships andstudentships to get them startedin a career in MS research.

The key principles guiding the MSSociety research program are:excellence and relevance to MS.The MS Society will support onlythe best research projects andthe best young scientists.

The research projects must alsohave direct relevance to MS. If aproject is excellent, but hasnothing to do with multiplesclerosis, it will not be funded.Currently, MS research is in thesemajor areas: myelin repair,genetic susceptibility,immunology, virology, MRItechnology, health and treatmenteffects.

How MS Research Is Funded

MRI: Window into MSScientists use manytools to take snapshotsof what is happening inthe brain during MS.One of the mostsensitive of these toolsis magnetic resonanceimaging (MRI) which

generates two-dimensional images of thebody’s internal structures. MRI contrastswhite matter (myelin) from grey matterand cerebral spinal fluid, and is sosensitive that it can distinguish betweenhealthy brain tissue and lesions in aperson with MS. Magnetic resonancespectroscopy (MRS) is also a usefulimaging tool which compiles chemicalinformation about healthy and diseasedtissues.

As non-invasive techniques, MRI and MRScan be routinely used to follow individualswith MS on an ongoing basis. Incombination, these techniques form apowerful way to monitor how MS lesionsrespond to different therapies. Scientistsare constantly devising new and improvedMRI and MRS techniques with the goal ofcapturing more detailed snapshots ofwhat happens at different stages of MS.Better imaging tools will improvediagnosis, monitoring and management ofclinical symptoms, and treatments forpeople with MS.

Douglas Arnold, MD, and Bruce Pike, PhD McGill University $342,383 (April 1, 2005 – March 31, 2008)

Imaging demyelination andremyelination in MS

During MS, the myelin insulationsurrounding nerve fibres (axons) isdamaged. Short-term myelin loss cancause acute symptoms of relapse whileprolonged myelin loss may lead to thedeath of nerve axons, causing permanentdisability. The relationship betweenmyelin loss, nerve axon injury anddisability can be investigated by usingimaging techniques that measure myelinloss and repair.

Damage to the brain during MS can beseen as white spots on conventionalmagnetic resonance images (MRI).Unfortunately, MRI spots are difficult tointerpret as they still can’t be matchedwith the degree of injury to the brain orto the clinical symptoms that develop.Drs. Arnold and Pike’s research goal is todevelop better magnetic resonanceimaging techniques which measure myelinloss and repair over time in acute MSlesions. Magnetization transfer imaging(MTI) is a newer magnetic resonanceimaging technique that is superior to MRIin that it gives specific information aboutdamage to myelin. Using MTI, Drs. Arnoldand Pike have already been able to clarifythe timeline of myelin loss in chronic and,to a lesser extent, in acute MS lesions.

Their continued research efforts should beable to show whether MTI can besuccessfully used to monitor futuretherapies aimed at promoting myelinregrowth in people with MS.

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Alex MacKay, MD and David Li, MD University of British Columbia $276,810 (April 1, 2004 – March 31, 2007)

In vivo serial studies of pathology inmultiple sclerosis integrating theresults from several magneticresonance techniques

In MS, damage to myelin may causeattacks (relapses) where vision,sensation, coordination and strength aretemporarily or permanently lost. With thedevelopment of magnetic resonance (MR)techniques researchers are no longerconfined to post-mortem observation butcan follow physical and chemical changesto myelin in people living with MS.

Drs. MacKay and Li are using a variety ofdifferent MR techniques to pinpoint whenmyelin loss occurs in MS lesions after theblood-brain-barrier becomes leaky,allowing immune system cells into thebrain and spinal cord. They made somegood technical progress during the lastperiod funded by the MS Society. Theresearchers developed a better MRtechnique that takes advantage of watertrapped in the myelin layers to generate avery high resolution myelin map of asingle slice in the brain. They also have anew magnetic resonance spectroscopy(MRS) scanner that gives higher quality2D images than those obtained inprevious years. With their new andimproved MR techniques, they are using anumber of markers to gauge myelin loss,regrowth and changes in ‘normalappearing’ white matter of the brain.

By relating clinical disability with theobserved physical and chemical changesto myelin, they should be able to predictsome of the factors that contribute tofunctional loss in people living with MS.

Ross Mitchell, PhD University of Calgary $244,451 (April 1, 2006 – March 31, 2009)

Texture analysis of myelin sensitiveMRI

Magnetic resonance imaging (MRI) is avery sensitive diagnostic test. AlthoughMS lesions are reliably visualized usingMRI, it is often unclear how lesions relateto clinical status in people with MS.Great advances have been made inmedical imaging over the last twodecades, but the interpretation of thisnew digital data is still somewhatsubjective.

During the last period funded by the MSSociety, Dr. Mitchell made considerableprogress. In 2003, he introduced a newtype of analysis to the medical imagingcommunity, resulting in numerous highprofile publications. In the currentproject, Dr. Mitchell builds a uniquecomponent into his new analysis; namely,the ability to measure the ‘texture’ of MRimages in people with MS. Texture refersto an intuitive, yet measurablecharacterization of the local pattern of anMR image. Using texture analysis, Dr.Mitchell is analyzing MRI exams fromnormal volunteers to develop markers ofmyelin health throughout the normalbrain. These markers can then be usedto gauge how new treatments affect thebrain of people with MS.

Dr. Mitchell’s MRI texture analysis toolshould improve the power and efficiencyof clinical trials evaluating new MStherapies.

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Wayne Moore, MD, StanleyHashimoto, MD, David Li, MD, RobertNugent, MD, and Alex MacKay, PhD University of British Columbia$247,680 (April 1, 2005 – March 31, 2007)

The pathological basis of magneticresonance imaging in multiplesclerosis

Magnetic resonance imaging (MRI) is avery sensitive technique for detectingplaques in MS. In recent years, MRIstudies have also detected otherabnormalities in widespread areas of thebrain and spinal cord. It is unclear whatchanges in the brain tissue might bringabout these diffuse abnormalities andhow such changes relate to new lesionformation.

Dr. Moore and his colleagues continue tostudy this phenomenon by examiningMRI-detected changes in dirty-appearingwhite matter (DWM) and normal-appearing white matter (NAWM), both ofwhich are regions of white matter withoutMS lesions. Since their last MS Societygrant, this research team has madeconsiderable progress. They noted atendency for demyelinated plaques tooccur in DWM, suggesting that it is thearea where white matter plaques develop.They are investigating DWM in moredetail and comparing DWM and NAWM formyelin loss, lipid abnormalities, nervefibre loss, and blood vessel integrity. Theresearchers are also looking to see ifthere is a breakdown of the blood–brain-barrier in DWM, thereby allowing a wayfor circulating cells and other substancesto enter the DWM and cause damage.

These findings will aid in understandinghow and where an MS plaque developsand point to the factors responsible forthe progression of disease.

Managing MS BetterToday

Multiple sclerosistypically affects youngadults in the prime oflife, between 15 and 40years of age. Themajority of people withMS start out with arelapsing-remitting form

of the disease and go on to develop amore progressive form. Regardless of thetype of MS an individual has, he or shemust live with the disease for a long time.

Health research projects investigateproblems that people with MS encounterduring daily life. They focus on a numberof areas including health economics,population health, and psychosocial andbehavioural issues. Rather thaninvestigating the causes of MS, health-related research measures the impact ofMS on all aspects of health, and strives toimprove the quality of life for people livingwith the disease.

Anthony Feinstein, MD, PhD, Danielle Tisserand, PhD, and Paul O’Connor, MD St. Michael’s Hospital, University of Toronto $144,340 (April 1, 2005 – March 31, 2007)

Multiple sclerosis and depression: An MRI diffusion tensor imagingstudy

Almost 50% of people with MS experienceclinically significant depression during thecourse of their lives. The reason for thisis still unclear. Using MRI, Dr. Feinstein’steam previously showed that MS lesionsand shrinkage in certain regions of thebrain increase the risk of depression.

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However, these MRI results do not alwayspredict who will develop depression,suggesting inherent limitations inconventional MRI techniques.

Dr. Feinstein and his colleagues areadding diffusion tensor imaging (DTI) totheir detection arsenal to help addressthe issue of depression in MS. They areusing both conventional MRI and thenewer DTI technique to look for brainfactors associated with mood change. Todo this, the researchers are performingMRIs and DTIs on people with MS whoeither do or do not suffer from moodchanges.

The results of this research will havevaluable clinical impact. If depression canbe more firmly linked to brainabnormalities, clinicians will moreconfidently choose drug intervention asthe best treatment option. On the otherhand, if brain abnormalities detected byMRI and DTI explain only a minority ofthe cases where depression occurs,clinicians can proceed with psychosocialtreatment options.

Helen Tremlett, PhD, and Joël Oger, MD University of British Columbia $70,360 (April 1, 2004 – March 31, 2006)

The impact of beta-interferon therapyon multiple sclerosis: effectivenessand toxicity

MS is a chronic disease of the brain andspinal cord and one of the most commonreasons for severe disability in youngadults. Although there is still no cure,beta interferon therapies are available totreat MS. During a post-doctoralfellowship at UBC funded by the MSSociety, Dr. Tremlett observed that oneparticipant in a clinical trial of betainterferon developed liver failure andneeded a transplant. This person was alsotaking other medications at the same

time. Such observations led Drs. Tremlettand Oger to focus their current researchon the effectiveness of beta interferon andits potential for liver toxicity in peoplewith MS.

Because people with MS frequently usemultiple medications, Drs. Tremlett andOger are investigating the risk of livertoxicity from combining differentmedicines with beta interferon. They arealso assessing how often people with MS,not taking beta interferon, show abnormalliver test results. Another question iswhether the existence of other diseasesalso increases the likelihood of abnormalliver tests in people with MS. Finally, theresearchers plan to monitor how long-term use (over three years) of betainterferon affects disability in people withMS.

The goal of this research is to providebetter counselling and monitoring ofpeople with MS. Ultimately, Drs. Tremlettand Oger hope to reduce the number ofpeople having to stop treatment becauseof abnormal liver tests.

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Attracting new and talented

young scientists to the MS

research field is a challenge

that the MS Society takes very

seriously, and the various

personnel support awards are a

major incentive to students and

just-graduated researchers.

Reinhold Vieth, PhD, University of Toronto; A. Dessa Sadovnick, PhD, Universityof British Columbia; and GeorgeEbers, MD, University of Oxford $276,000 (April 1, 2006 – March 31, 2008)

Vitamin D levels in MS patients andtheir families

There is growing evidence that theinterplay between genes and theenvironment determines susceptibility toMS. One very striking clue about a rolefor the environment is that MS increasesthe farther away one lives from theequator. In Australia, the incidence of MSin temperate Tasmania is five timesgreater than in subtropical Queensland,despite the similar ethnic origins of theinhabitants. Very few foods containvitamin D so geographical location woulddefinitely influence vitamin D levelsbecause people living further away fromthe equator don’t get enough sunlight(UVB) for the skin to make vitamin Dduring winter months.

The focus of the research is to comparevitamin D levels in people with andwithout a risk for MS. The researchers aremeasuring the levels of vitamin D inidentical and fraternal twins, in peoplewith MS and their families (3,500individuals in total), and in mothers withmultiple children having MS. Improvingvitamin D nutrition could be implementedfairly easily and safely, and in a cost-effective way.

If they find a link between vitamin D andMS, then the research may provide theevidence needed to begin clinical studiesof vitamin D-based strategies to preventMS.

Collaboration toSpeed Results Multiple Sclerosis Scientific ResearchFoundation Research Grants

The MS ScientificResearch Foundationwas established in 1973with an initialinvestment of $1,000.Over the years withfunding from the MS

Society of Canada, the Foundation hasbecome the largest funder in the worlddedicated strictly to MS research.Currently, the MS Scientific ResearchFoundation is funding four flagshipcollaborative research initiatives. It alsofunds small pilot research projects whichallow investigators to pursue newinnovative approaches to MS research.

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The MS Society and the related

MS Scientific Research

Foundation are able to continue

this level of funding

commitment thanks to the

ongoing support of individual

donors, corporate partners and

MS Society chapters.

Remyelination in Multiple Sclerosis:Enhancing Intrinsic Repair

Phase II: $2.25 million over three yearsfrom the Multiple Sclerosis ScientificResearch Foundation – Approved April2005

Principal InvestigatorsJack Antel, MD, Montreal NeurologicalInstitute, McGill University Samuel Weiss, PhD, Hotchkiss BrainInstitute, University of Calgary Moses Rodriguez, MD, Mayo Clinic,Rochester, MN.

Destruction of myelin in the brain andspinal cord is a major feature in multiplesclerosis. Cells from the immune systemattack myelin, the substance thatsurrounds and protects nerve fibres in thecentral nervous system. Myelin damage isoften severe, leaving people with long-term disability. Myelin repair andreplacement does occur but the extent islimited.

Phase II of this large, collaborativeresearch project is seeking ways to findout if there are cells in the body’s owncentral nervous system that can betransformed into a cellular repair team tomend damage to myelin caused bymultiple sclerosis. The cells theresearchers are targeting are called stemcell progenitor cells. They are cells withinthe body that have yet to become fullyspecialized, so the goal with this projectis to stimulate them to becomeoligodendrocytes, the cells that makemyelin.

Drs. Antel, Weiss and Rodriguez havechosen to use the body’s own stem cellprogenitors from the adult centralnervous system. This avoids invasivesurgical procedures and should overcomethe limitations in the numbers of cellsavailable for transplantation and theproblem of directing the cells to the sitesof injury. This multi-disciplinary team ofneurologists and basic scientists believethe approach of using the body’s own

cells to repair myelin damage isparticularly applicable in a disease inwhich injury can occur in any part of thecentral nervous system. The research istargeting stem cell progenitors that havealready been located within the body anduses various proteins and hormones toentice them to the damaged parts of thebrain and spinal cord that needremyelination.

The researchers have also pioneered newways of using magnetic resonanceimaging to non-invasively measure theproduction of new myelin and the rate ofrecovery from MS attacks. The ability togenerate myelin and measure whetherthe new myelin is wrapping effectivelyaround nerve fibres is key to reducingdisability caused by MS.

Essentially, the research teams at thethree centres are looking for an “on”switch that can kick-start theremyelination process. If successful, theyhope to identify specific strategies formyelin repair and turn their findings intoclinical trials to determine whetherremyelination will lead to an actualdecrease in disability in people with MS.

Canadian Collaborative Project onGenetic Susceptibility to MultipleSclerosis – Phase IV

Phase IV: $3.16 million over three yearsfrom the Multiple Sclerosis ScientificResearch Foundation – Approved April2004

Principal InvestigatorsA. Dessa Sadovnick, PhD, University ofBritish Columbia George Ebers, MD, University of Oxford

Co-InvestigatorNeil Risch, PhD, Stanford University,California

Multiple sclerosis is not an inheriteddisease, but it does tend to occur moreoften in families where other membersare affected. Women are more than twice

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as likely to develop MS as men. Althoughsymptoms vary greatly, even betweenidentical twins, more and more researchshows that families may share commongenes making them more susceptible toMS.

Much of the information acquired fromgenetic studies is obtained by looking atspecial groups of people, like twins,siblings, half-siblings and adoptees.Within these groups, scientists areidentifying susceptibility genes anduncovering the normal function of thosegenes. Good candidate genes for studyare those controlling myelin growth andcell-to-cell communications. Takentogether, the knowledge gained fromgenetic studies is helping researchersdesign therapies that might be capable ofcontrolling susceptibility genes in peoplewith MS.

Since the initial study began in 1993,much progress has been made inunderstanding the relative roles ofgenetic (inherited) and environmental(non-genetic) factors, both in the overallcause of MS and the predisposition to MSamong family members. Thisunprecedented cooperative study involvesmore than 21,000 people with MSregistered at 18 MS clinics acrossCanada.

The Canadian Collaborative GeneticSusceptibility Study has confirmed thatMS is a complex disease. Several genesare involved in causing MS and ofteninteract with each other. Environmentalfactors are also important and act at apopulation level to strongly influencewhether people who are geneticallysusceptible will develop MS.

The study has provided a number ofimportant insights from Phases I, II andIII.

• It has been clearly shown that theincrease of MS among relatives ofaffected individuals is because theyshare genetic material (DNA) and

not because they share a commonfamily environment.

• Studies of affected sibling pairs andtheir parents have suggested thatsome families may have moregenetic factors involved in causingMS compared to other families.

• Studies of partners who both haveMS support the impression that MSis not an infectious disease sincethe occurrence of both partnershaving the disease does not happenmore often than expected based ongeneral population data.

Molecular genetic studies are continuing.Some specific candidate genes have beeneliminated and others are still beinginvestigated.

In Phase III, the researchers looked atthe molecular genetics, clinical genetics,genetic epidemiology and environmentalfactors which may play a role in causingMS. They specifically focused on:

• Environmental factors includingearly life events and diseases,exposure to sunlight, patterns ofmigration, birth order and month ofbirth.

• Continued genome screening andthe search for “candidate” genes.This process is accelerating quicklywith access to data from theHuman Genome Project and newtechnology for screening for genesin populations.

Phase IV is developing further the geneticepidemiology and environmental factorsand, at the same time, directly applyingknowledge gained to date for people withMS and their families through geneticcounselling. A study geared towardsprevention of MS may grow out of PhaseIV.

In Phase IV, the researchers are pursuingincreasingly practical applications,specifically:

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• Extending knowledge of the role ofgenetics and carefully examineenvironmental factors;

• Examining the incidence of MS overtime;

• Using this knowledge as the basisof a Canadian prevention study inMS, which would be the first of itskind in the world.

Bone Marrow Transplantation Project

Full title: Targeting Multiple Sclerosisas an Autoimmune Disease withIntensive Immunoablative Therapyand Immunological Reconstitution – A Potential Curative Therapy forPatients with Predicted PoorPrognosis MS

$4 million over six years from the MultipleSclerosis Scientific Research Foundation –Approved August 2000

Principal InvestigatorsHarold Atkins, MD, Bone MarrowTransplantation Program, Ottawa Hospital– General Campus Mark Freedman, MD, MS Research Clinic,Ottawa Hospital – General Campus

The Multiple Sclerosis Scientific ResearchFoundation is funding a multi-centreproject to determine whethertransplanting bone marrow stem cells inpeople with MS can stop the disease. Ledby Dr. Mark Freedman (MS neurologist)and Dr. Harold Atkins (bone marrowtransplant physician), both at theUniversity of Ottawa, the study willinvolve 36 people with rapidly progressingmultiple sclerosis who are likely tobecome severely disabled. Twenty-four ofthe participants will receive bone marrowtransplantation while 12 other people withthe same kind of MS but who do not wishto have the procedure will be the controlgroup. Recruitment began in October2000. Treatment centres for the study arelocated in Ottawa, Toronto and Montreal.

Bone marrow transplantation is usedfrequently to treat leukemia. In a verysmall number of people who have bothMS and leukemia, MS symptomsimproved following the bone marrow stemcell transplant. This project should allowinvestigators to determine if bone marrowtransplantation is an effective treatmentin a group of closely matched people withmultiple sclerosis.

Equally important, should the procedurenot fully stop the disease process, isgaining information about what triggersare present and what changes to theimmune system occur at the beginning ofdisease activity. The researchers aremonitoring closely for signs of diseaseactivity in the participants at all stages ofthe procedure from enrolment to the endof the study. Monitoring will includecomplex immune system tests andtracking of certain immune-relatedgenetic changes in the hope of unveilingparticular genes that might contribute togenetic susceptibility.

Development of MS in Children

Full title: Prospective Study of theClinical Epidemiology, Pathobiologyand Neuroimaging Features ofCanadian Children with ClinicallyIsolated Demyelinating Syndromes

$4.3 million over five years from theMultiple Sclerosis Scientific ResearchFoundation – Approved April 2004

Principal Investigators Brenda Banwell, MD, Hospital for SickChildren, Toronto Douglas Arnold, MD, MontrealNeurological Institute, MontrealAmit Bar-Or, MD, Montreal NeurologicalInstitute, Montreal A. Dessa Sadovnick, PhD, University ofBritish Columbia, Vancouver

This ground-breaking Canadian study willexamine children who have experiencedan initial attack suggestive of MS, also

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known as clinically isolated syndrome(CIS). This five-year, prospectivepaediatric MS study has 22 Canadiancentres participating in 17 cities,including: Victoria, Vancouver, Edmonton,Calgary, Saskatoon, Winnipeg, London,Hamilton, Windsor, Toronto, Kingston,Ottawa, Sherbrooke, Montreal, SaintJohn, Halifax and St. John’s. PaediatricCIS has never before been examined insuch detail. The study is possible throughthe development of the PaediatricDemyelinating Disease Network, anextensive Canada-wide network ofphysicians and scientists.

The goal of the study is to answer twoimportant questions: what is the cause ofMS and what is the risk of MS after aninitial attack of CIS.

• The cause of MS: By studyingpaediatric patients, who are closest tothe biological onset of the disease,researchers hope to identify thefactors most important in diseaseinitiation – the earliest events in MSpathobiology.

• The risk of MS after a first attack:By carefully following children whohave experienced an initial attack(known as clinically isolatedsyndrome – CIS), researchers hopeto understand why some patientshave a single attack (CIS) andnever progress to MS, while othershave multiple attacks leading to thediagnosis of MS.

The study has three pillars: clinicaland genetic epidemiology,pathobiology and neuroimaging.

1) Clinical and genetic epidemiology

• To identify predictors of thedisease, the researchers will definethe clinical features, demographicsand genetic epidemiology ofchildren with CIS, and of those whoprogress to MS. Currently, there areno childhood predictors for MS.

• To increase awareness of childhood-onset MS and facilitate promptdiagnosis the researchers willidentify the features of MS inchildren, and characteristicspredictive of MS risk following afirst (CIS) attack.

2) Pathobiology

• To define the earliest immunologicalevents that occur at the time of thefirst (CIS) attack, investigators willstrive to identify both the triggersand initial targets of the immunecell response.

• To define those immune responsesassociated with, or predictive of,the risk for further attacks leadingto the diagnosis of MS.

3) Neuroimaging

• MRI (magnetic resonance imaging)is currently available to assist in MSdiagnosis, and in the prediction ofMS risk following CIS in adults. Bystudying MRI characteristics in thepaediatric study population, theresearchers will:

- Create diagnostic MRI criteria forMS in children, facilitatingdiagnosis.

- Determine if particular MRIfeatures are predictive of MS riskin children with CIS.

- Utilize newer MRI technologies toexplore whether there arefundamental differences in thebrain white matter (myelin) ofchildren destined for MS.

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Programs to AttractNew Scientific Talent

Dr. Donald Paty Career DevelopmentAwards

The Multiple SclerosisSociety provides a limitednumber of Dr. DonaldPaty Career Development

Awards for individuals holding a doctoratedegree and who have demonstrated acommitment to a career in MS research.

Dr. Donald Paty had a long anddistinguished career in Canada as an MSneurologist and researcher. He headedthe MS Clinics at the University ofWestern Ontario and the University ofBritish Columbia. His leadership in patientcare, clinical trials and MRI research haveinspired his colleagues around the world.

Total approved for Awards: $900,000

Dr. Amit Bar-Or Montreal Neurological Institute Category: Immunology Renewal: $50,000 for each of three yearsbeginning July 1, 2004

Dr. Paula Foster Robarts Research Institute, London ON Category: MRI techniques New: $50,000 for each of three yearsbeginning July 1, 2004

Dr. Fabrizio Giuliani University of Alberta Category: Immunology New: $50,000 for each of three years Beginning July 1, 2006

Dr. Ross Mitchell University of Calgary Category: MRI techniques Renewal: $50,000 for each of three yearsbeginning July 1, 2006

Dr. Alexandre Prat Hôpital Notre-Dame, Montreal Category: Immunology New: $50,000 for each of three yearsbeginning July 1, 2004

Dr. Helen Tremlett University of British Columbia Category: Health research New: $50,000 for each of three yearsbeginning July 1, 2004

Postdoctoral Fellowships

The Multiple Sclerosis Society providesfunding for investigators who hold MD orPhD degrees to pursue additional study inan MS related area. The grants are forone year with an opportunity for renewal.

Total approved for PostdoctoralFellowships: $594,500

Fatemeh Afifiyan, PhD Hospital for Sick Children, Toronto Supervisor: Dr. Hans-Michael Dosch Renewal: $39,000

Smriti Mona Agrawal, PhD University of Calgary Supervisor: Dr. V. Wee Yong New: $39,000

Claudia Calder, PhD Montreal Neurological Institute Supervisor: Dr. Amit Bar-Or New: $39,000

Peter Darlington, PhD McGill University Supervisor: Dr. Timothy Kennedy Renewal: $39,000

Julie Fotheringham, PhD National Institute of Health (Bethesda,MD, USA) Supervisor: Dr. Steven Jacobson Renewal: $39,000

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Yunfei Gao, PhD University of Toronto Supervisor: Dr. Jennifer Gommerman New: $39,000

Isaias Glezer, PhD Laval University Supervisor: Dr. Serge Rivest Renewal: $39,000

Andrea Hebb, PhD Dalhousie University Supervisor: Dr. George Robertson Renewal: $39,000

Yukie Hirahara-Wada, PhD Hospital for Sick Children, Toronto Supervisor: Dr. Joan Boggs Renewal: $39,000

Bradley Kerr, PhD McGill University Supervisor: Dr. Samuel David Renewal: $39,000

Madeline Pool, PhD Ottawa Health Research Institute Supervisor: Dr. Alyson Fournier Renewal: $39,000

Dafni Reiss, PhD BC Cancer Research Agency, Vancouver Supervisor: Dr. Dixie Mager New: $39,000

Viktor Skihar, MD, PhD University of Calgary Supervisor: Dr. V. Wee Yong Renewal: $48,500

Nicolas P. Turrin, PhD CREMO, Montreal Supervisor: Dr. Serge Rivest Renewal: $39,000

Karolina Wosik, PhD Hôpital Notre-Dame, Montreal Supervisor: Dr. Alexandre Prat Renewal: $39,000

Research Studentships

The MS Society provides funding forstudents who are working toward MSc,PhD or related degrees in areas relevantto MS research. The studentships aredesigned to encourage young scientists toconsider a career in MS research. Thegrants are for one year with anopportunity for renewal.

Total approved for Studentships:$786,666

Azadeh Arjmandi University of British Columbia Supervisor: Dr. Katarina Dorovini-Zis New: $20,000

Jennifer Berard McGill University Supervisor: Dr. Samuel David Renewal: $20,000

Shawn Beug Ottawa Health Research Institute Supervisor: Dr. Valerie Wallace Renewal: $20,000

Jennifer Beveridge University of Ottawa Supervisor: Dr. Mark Freedman New: $20,000

Olivia Bibollet-Bahena McGill University Supervisor: Dr. Guillermina Almazan Renewal: $20,000

Thor Bjarnason University of Calgary Supervisor: Dr. Ross Mitchell Renewal: $20,000

Michelle Brucal Wayne State University, Detroit, MI (USA) Supervisor: Dr. John Kamholz Renewal: $20,000

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Katia Charland McGill University Supervisor: Dr. Christina Wolfson Renewal: $20,000

Zhihong Chen University of Ottawa Supervisor: Dr. Mark Freedman New: $20,000

Carol Anne Chénard Lady Davis Research Institute, Montreal Supervisor: Dr. Stéphane Richard Renewal: $20,000

Rowena Cua University of Calgary Supervisor: Dr. V. Wee Yong Renewal: $20,000

Danielle Duszczyszyn McGill University Supervisor: Dr. David Haegart Renewal: $20,000

Farnaz Forghani McGill University Supervisor: Dr. Alan Peterson Renewal: $20,000

Ebrima Gibbs University of British Columbia Supervisor: Dr. Jöel Oger New: $20,000

Elizabeth Girolami McGill University Supervisor: Dr. Samuel David New: $20,000

Angelika Goncalves DaSilva University of Calgary Supervisor: Dr. V. Wee Yong Renewal: $20,000

Jeffrey Haines McGill University Supervisor: Dr. Guillemina Almazan New: $18,000

Shireen Hossain McGill University Supervisor: Dr. Guillermina Almazan Renewal: $20,000

Igal Ifergan Notre-Dame Hospital, Montreal Supervisor: Dr. Alexandre Prat Renewal: $20,000

Carolyn Jack Montreal Neurological Institute Supervisor: Dr. Jack Antel Renewal: $20,000

Hania Kébir University of Montreal Supervisor: Dr. Alexandre Prat New: $20,000

Melissa Kehler University of Regina Supervisor: Dr. HeatherHadjistravropolous New: $18,000

Samantha Kimball University of Toronto Supervisor: Dr. Reinhold Vieth New: $18,000

James Knight Ottawa Hospital Research Institute Supervisor: Dr. Rashmi Kothary New: $18,000

Kaveh Koochesfahani University of British Columbia Supervisor: Dr. Katarina Dorovini-Zis New: $20,000

Antonia Kuznetsova Dalhousie University Supervisor: Dr. John Fisk Renewal: $20,000

Genevieve Lacroix McGill University Supervisor: Dr. Stéphane Richard New: $20,000

Lorraine Lau University of Calgary Supervisor: Dr. V. Wee Yong New: $20,000

Karen Lee Ottawa Health Research Institute Supervisor: Dr. Rashmi Kothary Renewal: $20,000

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Kenneth Liu University of British Columbia Supervisor: Dr. Katerina Dorovini-Zis Renewal: $20,000

Jason Millward Montreal Neurological Institute Supervisor: Dr. Trevor Owens Renewal: $20,000

Craig Moore Dalhousie University Supervisor: Dr. George Robertson Renewal: $20,000

Abdi Musse University of Guelph Supervisor: Dr. George Harauz Renewal: $20,000

Ayman Oweida University of Western Ontario Supervisor: Dr. Paula Foster Renewal: $18,000

Sathyanath Rajasekharan McGill University Supervisor: Dr. Timothy Kennedy Renewal: $20,000

Debra Robson University of Guelph Supervisor: Dr. George Harauz New: $20,000

Philippe Saikali Montreal Neurological Institute Supervisor: Dr. Jack Antel New: $20,000

Leslie Summers DeLuca University of Toronto Supervisor: Dr. Jennifer Gommerman New: $20,000

Nazi Torabi McGill University Supervisor: Dr. Stéphane Richard Renewal: $20,000

Melissa Welsh University of Western Ontario Supervisor: Dr. Stephen Karlik New: $16,666

Pilot Research GrantsPilot Research Grants Pilot researchgrants are available to fund small,innovative research projects. They aretargeted at quickly looking at new,untested ideas to gain preliminary datathat can then be used for a full researchproject application. The pilot researchprogram is supported by the MS ScientificResearch Foundation, which is related tothe MS Society of Canada.

• Trevor Owens, PhD, McGillUniversity Biomedical Research – Role ofInhibitors of Apoptosis (IAPs) inautoimmune demyelienatingdisease $35,000 – Approved: February2005

• Tom Tombaugh, CarletonUniversityHealth Research – Detectingcognitive impairments using thecomputerized test of informationprocessing $13,600 – Approved: June 2005

• Chris Proud, University of BritishColumbia Biomedical Research – Targetedtransgenic mouse model for adegenarative disease, vanishingwhite matter $35,000 – Approved: June 2005

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Glossary 2006Adhesion molecule – A protein thatpromotes the binding of one cell toanother or to the extracellular matrix.

Antibody – A protein made by a plasmacell (activated B cell) that protects thebody against foreign invaders likebacteria and viruses.

Antigen – A substance that is bound byantibodies. The name ‘antigen’ arisesfrom the ability to generate antibodies.Viral and bacterial molecules and eventhe body’s own molecules can beantigens.

Angiogenesis – The formation of newblood vessels.

Antigen presenting cell – A specializedcell that sticks pieces of antigencombined with self ‘display’ molecules onits surface for passing immune cells tosurvey. Dendritic cells, macrophages andB cells are the main antigen-presentingcells.

Astrocyte – A support cell in the centralnervous system (CNS) that attaches toboth nerve cells and blood vessels;provides metabolic, nutritional andphysical support; makes scars ondamaged tissue during MS.

Axon – The long slender nerve fibreextending from a neuron cell body.Synonymous with nerve fibre.

B cell – An antibody-making lymphocyte(white blood cell) originating in the bonemarrow.

Blood brain barrier (BBB) – A bloodvessel barrier lined with tightly connectedendothelial cells; prevents most largemolecules and cells found in the bloodfrom entering the brain tissue.

Central nervous system (CNS) – The region composed of the brain and the

spinal cord; all parts of the CNS can beaffected by multiple sclerosis.

Cerebral spinal fluid (CSF) – The fluidbathing the surfaces of the centralnervous system.

Chemokine – A type of cytokine thatacts as a beacon to attract white bloodcells from the circulation into an injuredor infected site.

Cytokine – A protein messenger moleculethat influences the actions of immunesystem cells; also called a lymphokine orinterleukin (IL). There are many differentcytokines, each acting only on cells thathave receptors for that cytokine.

Demyelination – The process duringwhich myelin is stripped from nerve fibres.

Dendritic cells – A white blood cell thatis bone-marrow derived and specializes inpresenting (displaying) antigen to T cells.

Differentiation – A series of steps thatcells go through to reach their maturestate.

DNA (deoxyribonucleic acid) – Thecode of genetic instructions that shapesthe development of every individual.DNA is shaped as a double helix and ismade up of nucleic acid-sugar complexesloosely bound to proteins.

Endothelial cell – A type of cell thatlines the heart and blood vessels of thecirculatory and immune systems;endothelial cells lining the blood vessels ofthe brain form the blood brain barrier(BBB).

Expanded Disability Status Score(EDSS) – Expanded Disability StatusScore is a test for measuring thedisability level of a person with MS; alsoknown as the Kurtkze Scale, after Dr.John Kurtzke.

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Experimental allergicencephalomyelitis (EAE) – An MS-likedisease created in laboratory mice afterthey are injected with either CNS tissueor a derivative of myelin basic protein.

Gene – A stretch of DNA that containsthe genetic code for making bodyproteins; located on chromosomes.

Glial cell – A support cell in the nervoussystem; e.g. oligodendrocytes, astrocytesand microglial cells in the central nervoussystem and Schwann cells in theperipheral nervous system.

Health Related Quality of Life (HRQL)– A measurement of the quality of life ofpeople with MS based on patient-perceived functional status and well-being.

Immunoglobulin – The membrane-bound version of antibody that bindsantigens and signals the B cell to secreteantibodies.

Inflammation – The normally protectivelocal immune response to infection orphysical/chemical injury leading to tissuedamage; characterized by swelling,redness, heat and pain, and accumulationof fluid, white blood cells and plasmaproteins; loss of function may occur.

Interferons (IFN) – Cytokines that helpcells to fight viruses. Alpha interferon andbeta interferon are made by white bloodcells, fibroblasts and other cells.(Manufactured versions are useful as MStreatments.) Gamma interferon isproduced by inflammatory T cells andnatural killer cells and its main action isto trigger macrophages to help fightinfections. Gamma interferon makes MSworse.

Lipid – A molecule, such as a fat, fattyacid or soap; also refers to the ability ofmolecules to be fat soluble.

Lymphocytes – White blood cells (Bcells, T cells and NK cells) of the immunesystem that fight specific infections.

Macrophage – A white blood cell that isamong the first immune system cells tofight invaders; also acts as an antigenpresenting cell. Macrophages are calleddifferent names depending where theyare found in the body (e.g. microglialcells in the brain).

Magnetic resonance imaging (MRI) –A technological tool that detects energyreleased from hydrogen atoms to createanatomical images. MR images of softtissue of the the brain and spinal cordclearly show MS lesions and may be usedto track disease progress.

Magnetic resonance spectroscopy(MRS) – A technological tool similar tomagnetic resonance imaging but providingchemical rather an anatomicalinformation. MRS is most useful whenevaluating trials of new treatments bymeasuring disease severity andprogression.

Mast cell – A white blood cell thatoriginates in the bone marrow; involvedin allergic responses.

Memory B cell – A type of B cell thatlives in the body for long periods of time;can be triggered to make antibodies.

Microglia – A macrophage-like cell thatresides in the brain; ‘eats’ cellular debrisand stimulates immune responses.

Monocyte – A type of white blood cellthat is called a monocyte while in theblood, and a macrophage upon enteringthe tissues.

Morphogen – A diffusable substancethat influences movement andorganization of cells during development.

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Multiple Sclerosis Quality of LifeInventory (MSQLI) – A questionnairedesigned to evaluate the burden ofdisease experienced by people with MS.

Myelin basic protein (MBP) – One ofthe main proteins found in myelin.

Myelin – A collection of proteins andlipids forming the myelin sheath; speedstransmission of signals along nerve fibres.

Myelination – The process during whicholigodendrocytes add new myelin to nervefibres (axons).

Myelin sheath – A covering of 1-200layers of myelin that surround nervefibres in the central and peripheralnervous system.

Nerve fibre – The slender, long branchextending from a neuron cell body, andcarrying nerve impulses to adjacent nervecells throughout the body. Most nervefibres are surrounded by the myelinsheath; also called nerve axon.

Neuroglial cell – A type of glial cell thatis a supporting, non-impulse generatingcell of the nervous system (e.g. astrocyteand oligodendrocyte).

Neuron – A cell within the nervoussystem that consists of a cell body andmembrane extensions, called dendriteswhen highly branched or axons whenminimally branched. Nerve impulsestravel along nerve fibres (axons).

Natural Killer (NK) cell – A type oflymphocyte (not T or B cells) that can killvirally infected cells and tumors.

Oligodendrocyte – A cell in the CNSthat makes and maintains myelin; wrapsits myelin-filled membranes around nervefibres (axons).

Peptide – A chain of amino acid buildingblocks strung together. The chain can be

two (di-) amino acids, three (tri-) aminoacids, or more (poly-) amino acids inlength.

Peripheral nervous system (PNS) –The region of the nervous system in thebody outside the brain and spinal cord.The PNS can be affected by MS.

Perivascular DC – A type of dendriticcell that is located around blood vessels.

Plaque – An area of myelin loss that ischaracteristic of multiple sclerosis.

PLP (Proteolipid Protein) – One of themajor proteins found in the myelinsheath.

Remyelination – The process duringwhich myelin is re-added to nerve fibresby oligodendrocytes or Schwann cells.

Schwann cell – The cell in the peripheralnervous system that makes andmaintains myelin.

T cell – A type of immune system cellthat fights infection. Two broad categoriesare alpha-beta and gamma-delta T cells.Alpha-beta subsets include helper T cells(CD4+) and killer T cells (CD8+).

T cell receptor (TCR) – A protein foundon the surface of T cells. Alpha-beta TCRbinds to bits of foreign peptides (orsometimes body peptides, like myelin)attached to cell surface ‘display’ proteinson antigen presenting cells.

Tumor necrosis factor (TNF) – Acytokine made by macrophages and someT cells that is toxic to tumor cells and playsrole in inflammatory responses. Two typesare TNF alpha and TNF beta.

Transgenic mice – Mice that containgenes from another source (animal orhuman); derives from ‘trans’ (other) and‘genic’ (genes).

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MS Society increases funding 1

Repairing Myelin, Protecting Nerves 2

Almazan and MushynskiBoggsBraun and GravelKennedyKotharyMoscarello and MastronardiPetersonPowerRichardStysWallaceYong

Immune System Has Key Role 8

AntelBar-OrDavid (2)Dorovini-ZisEaston and HaoFournier, AFournier, SGiulianiGommermanHaegert and GadagKarlikKubesOwensPratVallières

Looking at Viruses 17

Power

How MS Research is Funded 18

MRI: Window into MS 19

Arnold and PikeMacKay and LiMitchellMoore, Hashimoto, Li, Nugent and MacKay

Managing MS Better Today 21

Feinstein, Tisserand and O’ConnorTremlett and OgerVeith, Saovnick and Ebers

Collaboration to speed results 23

Remyelination in Multiple Sclerosis:Enhancing Intrinsic Repair 24Canadian Collaborative Project onGenetic Susceptibility to MultipleSclerosis – Phase IV 24Bone Marrow Transplantation 26Prospective Study of the ClinicalEpidemiology, Pathobiology andNeuroimaging Features of CanadianChildren with Clinically IsolatedDemyelinating Syndromes 26

Programs to Attract New Scientific Talent 28

Dr. Donald Paty Career DevelopmentAwardsPostdoctoral FellowshipsResearch StudentshipsPilot Research Grants

Glossary 2006 32

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INDEX

Summaries written by: Maya Chaddah. M.Sc., Immunology Editorial Advisor: Deanna Groetzinger, M.A.

Multiple Sclerosis Society of Canada National Research Department 700-175 Bloor St. E, North Tower Toronto, ON M4W 3R8

Telephone: (416) 922-6065 Toll-free: 1-866-922-6065 E-mail: [email protected] Website: www.mssociety.ca

This document is also available on the MS Society of Canada website in the MS Research section under Current Research Projects.

(Disponible en français)

Our MissionTo be a leader in finding a cure for multiple sclerosis and

enabling people affected by MS to enhance their quality of life.

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MultipleSclerosis

Society of Canada

The Multiple Sclerosis Society of Canada thanks the thousands of individualdonors, corporations and companies, and MS Society chapters and units for theirdedicated support of MS research. Together, we are making a difference.

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