Hollie's ECTRIMS 2009 notes

Hollie's Notes From The 2009 ECTRIMS Meeting In Dusseldorf

ECTRIMS meeting 9/9/09 - 9/12/09 (Dusseldorf, Germany)

Each year Accelerated Cure Project attends the annual congress for the European Committee for Treatment and Research in Multiple Sclerosis. We try to take notes on as many presentations as we can, write them up, and make them available on MSNews for anyone to read. Notes from this year's congress are below.

By the way, if you're interested in seeing the abstracts for the posters and presentations from this conference, you can do so by clicking here.

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Tuesday September 8, 2009

I left Boston Tuesday afternoon and had an uneventful flight to Dusseldorf with a connection through Paris. The only hiccup was being temporarily separated from my checked baggage which didn't make it to the connecting flight. It was a little strange traveling to an MS conference without Art, and being single-handed meant not being able to cover as many parallel sessions as we normally do. But I saw as much as I could!

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Wednesday September 9, 2009

After a shower and a short nap, I made my way to the conference center for the preliminary sessions (a satellite symposium and the Young Researchers' presentations).

Gadolinium enhancing lesions and remyelination (European Charcot Foundation)

Pluriformity of inflammation in gadolinium enhanced areas
F. Barkhof (Amsterdam, NL)

I caught just the tail end of this symposium. Dr. Barkhof reviewed evidence from a trial of the drug ibudilast in MS. Ibudilast is a PDE4 inhibitor, an anti-inflammatory drug. Imaging results from a 300 person trial showed no effect on active lesions, but the group given the drug had less brain atrophy than the group on placebo. Also, 14% of the lesions in the treated subjects vs 23% of those in the placebo subjects evolved to "T2 black holes." So perhaps ibudilast is neuroprotective in addition to being anti-inflammatory.

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Young researchers' session I

The incidence of meningeal B-cell follicles in secondary progressive multiple sclerosis: a neuropathological study of 96 cases

O.W. Howell, C. Reeves, R. Magliozzi, D. Carassiti, R. Nicholas, B. Radotra, S. Gentlemen, F. Roncaroli, F. Aloisi, R. Reynolds (London, UK; Rome, IT)

Recent discovery of clusters (follicles) of B cells in the lining of tissue outside the brain (meninges) has prompted further investigation into the frequency and implications of these structures. In this study, 114 SPMS cases from the UK MS tissue bank were analyzed for the presence of B cell follicles. 41% of the brains had these clusters. Subjects with these clusters on average had a more severe disease course, had an earlier age at onset, died younger, and were more likely to be female. Follicles were distributed throughout the meninges but were mostly located in the cerebral sulci (those inward folds in the outer part of the brain). Subjects with follicles had greater cortical demyelination but no increase in white matter demyelination compared with follicle-free subjects.

Massive up-regulation of immunoglobulin-related genes in the meninges of multiple sclerosis patients without evidence for Epstein-Barr virus infection
Ø. Torkildsen, C. Stansberg, S. Angelskår, E.J. Kooi, J. Geurts, P. van der Valk, K.M. Myhr, V. Steen, L. Bø (Bergen, NO; Amsterdam, NL)

Another interesting aspect of the B cell follicle story is the finding by the original investigators of Epstein-Barr virus in these clusters as well as in the brain tissue. Other investigators are doing their own experiments to see whether they can find EBV as well. This presentation described analysis of MS and control brain samples for B cells, EBV and gene expression. The investigators did not find evidence for EBV, nor did they see any B cell follicles. However, they did find T and B cells in the meninges of the MS subjects (not controls). Furthermore, they found that genes related to immunoglobulin (antibody) production were upregulated in the MS gray matter compared with controls. The team hypothesized that oligoclonal bands, which are evidence of a focused antibody response, may result from these few B cells in MS meningeal tissue.

Intravital imaging of TH17-mediated neuronal damage processes in experimental autoimmune encephalomyelitis
V. Siffrin, H. Radbruch, R. Glumm, E. Esplugues, H. Luche, R. Niesner, J.L. Rinnenthal, J. Herz, T. Leuenberger, H.J. Fehling, R.A. Flavell, F. Zipp (Berlin, DE; New Haven, US; Ulm, DE)

This presentation was based on the use of whizzy imaging technology for viewing interactions between immune cells and neurons in mice. These mice are genetically engineered so that their immune cells and neurons are labeled with different colored fluorescent markers. When the mice are anesthetized, a special camera can capture the movements of these cells. In normal mice that were imaged, the blood cells stayed in the blood vessels. In EAE mice, however, the camera showed T cells, e.g., Th17 cells, interacting directly with the neurons and even inducing apoptosis (cell death). The Th17 cells attacked the neurons whether or not they were specifically equipped to target neural antigens. The investigators further demonstrated that these immune/neural contacts induce calcium fluctuations in the axon, which can be reversed.

Effect of IL-27 on natural killer cell subsets and its potential significance in multiple sclerosis
A. Laroni, R. Gandhi, H.L. Weiner (Boston, US)

NK (natural killer) cells are an arm of the immune system that may play a protective role in MS althought they haven't received as much attention as T and B cells. The presenters were interested in the effect that IL-27 (produced by antigen presenting cells) would have on this cell type. Lab experiments showed IL-27 to increase longevity and decrease proliferation in NK cells. Also, IL-27 stimulated a class of cells called CD56 bright NK cells and this stimulation in turn resulted in inhibited proliferation of autoreactive T cells.

Characterisation of signal transduction pathways involved in glatiramer acetate (copolymer-1, Copaxone)-induced type II monocyte differentiation
N. Molnarfi, T. Prod'homme, M. Weber, S. Zamvil (San Francisco, US; Munich, DE)

Nobody yet really knows how Copaxone (glatiramer acetate) works in reducing relapses in MS. This group theorizes that it might induce a shift to a Type 2 immune response in monocytes, perhaps mediated by a receptor. Their presentation described some work to analyze the effect of GA on monocytes -- i.e., the molecules and pathways that appear to be activated when monocytes are stimulated by GA. (The abstract has some more detail if you're interested!)

Progression on the multiple sclerosis functional composite in MS: what is the optimal cut-off for the three test components (from a signal-to-noise perspective)?
L. Bosma, J. Kragt, L. Brieva, Z. Khaleeli, X. Montalban, C.H. Polman, A.J. Thompson, M. Tintoré, B. Uitdehaag (Amsterdam, NL; Barcelona, ES; London, UK)

The MSFC (MS functional composite) is a score to evaluate MS progression that takes into account walking (timed 25 foot walk), dexterity (9 hole peg test), and cognitive function (PASAT). It's a great idea to incorporate these different functional areas into one score; however, the problem is that each of these tests gives a numerical score that is continuous rather than discrete, raising the question of how much of a change is needed before someone can be deemed to have progressed. This group compared measurements of PPMS subjects taken two years apart and determined that a 20% change was optimal for the timed walk and 9 hole peg test. However, there was no reasonable cutoff for the PASAT.

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Young researchers' session II

Neurofilament light as a prognostic marker in multiple sclerosis
J. Salzer, A. Svenningsson, P. Sundström (Umeå, SE)

NFL is not only a major US sports organization, it's also a neural protein that can be detected in the spinal fluid of people with MS. The hypothesis analyzed in this study was that NFL levels could predict the prognosis of MS. A research team correlated NFL levels in CSF taken from MS subjects for diagnostic purposes with their EDSS scores measured an average of 14 years later. There was only a weak correlation across the board, but a stronger correlation in subjects with RRMS or RRMS with a recent relapse. High levels of NFL in people with RRMS were associated with a shorter time to SPMS conversion. No MRI images were available from around the time of the CSF draw, so it can't be determined whether the NFL levels were correlated with lesion numbers or other characteristics present at that time.

Antibodies against aquaporin-4 in neuromyelitis optica and NMO-related disorders
I. Ketelslegers, P. Modderman, D. Hamann, R.Q. Hintzen (Rotterdam, Amsterdam, NL)

Detection of anti-AQP4 antibodies is becoming a useful tool in diagnosing NMO and so it makes sense for groups who are doing this type of work to evaluate different methods and start standardizing them. This team compared two such methods (Fluorescence Immunoprecipitation Assay and a cell-based assay) by using them to evaluate samples from NMO, MS and ADEM samples. They found that the cell-based assay caught two NMO diagnoses that the FIPA didn't, but overall there was good concordance between the two techniques.

Validation of MR criteria to diagnose different types of leukoencephalopathies in a series of 75 consecutive patients
L. Bosqué Freeman, F. Sedel, C. Papeix, D. Galanaud, B. Granger, H. Chabriat, P. Labauge, A. Tourbah (Paris, Nîmes, FR)

A group of French neurologists developed a list of criteria that they use to distinguish vascular vs. inflammatory vs. metabolic disorder leukoencephalopathies, and boiled the list down to 7 to 10. The types of criteria considered included symmetry of lesions, signal intensity, and locations of lesions, among other factors.

T2w subtraction MR imaging in phase II MS trials: a powerful new outcome measure
B. Moraal, I. van den Elskamp, D. Knol, B. Uitdehaag, J. Geurts, H. Vrenken, P. Pouwels, R. van Schijndel, D. Meier, C. Guttmann, F. Barkhof (Amsterdam, NL; Boston, US)

Subtraction imaging compares a T2 image taken at one timepoint with that taken at a later timepoint, and subtracts out those lesions present at the beginning to give the number that developed between the two images. This technique might be helpful in clinical trials to reduce the cost and potential harm to subjects from repeated Gd+ imaging that sums up the number of new lesions seen in each scan. The team performed both types of analyses using images obtained over 9 months during a phase 2 trial of temsirolimus. They found that the monthly Gd+ MRI technique produced a higher lesion count than the subtraction technique did, but the results of the subtraction technique had a greater power to assess treatment efficacy.

Magnetic resonance evidence of the involvement of the striatal-thalamic-frontal cortex system in determining fatigue in multiple sclerosis
M. Calabrese, F. Rinaldi, I. Mattisi, P. Grossi, A. Favaretto, M. Atzori, L. Barachino, V. Bernardi, L. Rinaldi, P. Perini, P. Gallo (Padua, Albignasego, IT)

An imaging study compared MRI characteristics of MS subjects with and without fatigue to try to understand what causes MS-related fatigue. The investigators found that certain brain structures had reduced volumes in people with fatigue -- for example, the basal ganglia and frontal cortex were thinner on average. Other measurements were associated with individual components (physical and cognitive) of the fatigue score.

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That was it for the first day. I explored the city for a bit, enjoyed dinner outdoors at an Italian restaurant in the "Altstadt," and had a joyous reunion with my missing luggage back at the hotel.

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Thursday September 10, 2009

After a great hotel breakfast and a run on the footpath along the Rhine, I made my way back to the conference center. This involved a subway ride and a shuttle bus. Unfortunately the shuttle bus was not operating on a frequent schedule (I thought everything ran efficiently in Germany!), so I was a little late for the lecture below.

Plenary Session 1: Welcome address and ECTRIMS lecture

ECTRIMS lecture: Future challenges in MS
R. Hohlfeld (Munich, DE)

Dr. Hohlfeld's presentation discussed the main challenges facing MS research today. I missed the parts concerning ethics and risk/benefit ratios, so the first challenge I heard about was bridging the gap between MS and EAE. Dr. Hohlfeld described a new model of relapsing EAE based on a mouse with a nearly human T cell system in which EAE develops spontaneously (i.e., without injection of antigens). Gene expression and protein analysis, as well as new imaging techniques, are also helping bridge the gap.

Another challenge is how to encourage neuroprotection and repair. The research he described had to do with the use of genetically engineered mice to demonstrate the importance of BDNF (a neuroprotective factor) and the effects of macrophages on axons to cause swelling which either resolves or leads to axonal damage.

Tailoring therapy to patients appropriately is another goal. Dr. Hohlfeld mentioned a genetic mutation that's associated with MS that is also associated with a rheumatoid disease called TRAPS. This mutation appears to be associated with certain drug therapy side effects. Knowing more about genetic effects on drug efficacy and side effects would be very useful, especially with more options presumably becoming available soon.

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Parallel Session 1: Genetics – an update

A new era of genetics in understanding complex autoimmune disorders
S.J. Sawcer (Cambridge, UK)

Dr. Sawcer described the effects that the era of high-throughput screening has had on genetic research. Scientists have to apply a higher screening level to their results because when you can make hundreds of thousands of comparisons at one fell swoop, the associations you come up with are more likely to be false (due to chance) than true. As a result, the new significance level for deciding a result is true is p < 5 x 10(-7) -- compared with p < 0.05 which was the standard level for candidate gene studies. The new higher-powered studies are also requiring larger sample sizes, at least 2000 cases and 2000 controls.

Immune- and non-immune genes associated with MS
R.Q. Hintzen (Rotterdam, NL)

Several new genes beyond the well-studied HLA region have been identified in recent whole-genome screens. IL7R and IL2R have been confirmed, although the variants of these genes that have been implicated in MS are common and do not have a very strong effect on MS risk. Several other immune system genes have been associated with MS, as well as some CNS genes, such as KIF1b, an axonal transport gene.

Environment versus or together with genetics
G. Ebers (Oxford, UK)

MS is not strictly a genetic disease, although genes are definitely involved. Dr. Ebers reviewed a number of genetic and non-genetic factors that may interact to influence MS risk. For example, people with MS are more likely to have been born in April/May than in November, and month of birth has been found to correlate with HLA types in people with MS. Perhaps this correlation involves the vitamin D receptor element that was recently found to influence expression of the MS-associated HLA DRB1*1501 gene. He also noted the increasing female:male ratio in some countries (for instance, it's up to 3.5:1 in Canada and Scotland) and said that methylation of the HLA genes is another topic he's looking into.

Stress and the risk of multiple sclerosis
T. Riise, D.C. Mohr, K. Munger, I. Kawachi, A. Ascherio (Bergen, NO; Chicago, Boston, US)

Stress has been associated with an increased risk of MS relapse, and a study of bereaved parents in Norway has also reported an impact of stress on developing MS. A new study to investigate whether stress can trigger the onset of MS analyzed data from the Nurses' Health Study which has followed a cohort of nurses over time, monitoring health and other factors. No statistically significant effects on the development of MS were found for two factors: reporting of high stress in life and work, and reporting of abuse experienced during childhood and adolescence.

Predicting a diagnosis of multiple sclerosis with an aggregate Genetic Risk Score algorithm
P. De Jager, J. Cui, L. Chibnik, K. Simon, J. Reischl, S. Lehr, D. Bauer, J. Heubach, C. Pohl, R. Sandbrink, L. Petra, M. Tyblova, E. Havrdova, D. Horakova, D. Hafler, A. Ascherio, E. Karlson (Boston, US; Berlin, DE; Prague, CZ)

Dr. De Jager reported on the development of a genetic risk score that may be useful in identifying people at highest risk of MS. A predictive method for MS might help to prevent people from developing the disease, for instance if it encourages them to adopt behaviors thought to be protective. The current model is based on 16 gene variants; its predictive ability is enhanced by addition of other factors such as gender, EBV titers and smoking. The model will continue to be refined in hopes of increasing its capabilities.

Following this session, I went for lunch with two colleagues from Protagen, a company that is developing a diagnostic assay for MS and is using samples from our repository in its research. Protagen is based near Dusseldorf so it was great to have the opportunity to meet our "customers" face to face and learn more about their work.

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Parallel Session 4: Advances in therapy I

In search of innovative trial designs
L. Kappos (Basel, CH)

Dr. Kappos presented some interesting ideas having to do with clinical trial design. First of all, to help with enrollment in clinical trials, local neurology networks have been set up in France and Germany. These networks are composed of a referral center and local community neurologists who can refer their patients to the referral center for participation in trials. Second, although ethical concerns have been raised about including a placebo arm in trials (because that group of patients will not get any treatment), for drugs with unknown or potentially severe side effects it might be better to compare against placebo than an existing drug. It takes fewer subjects to prove efficacy when comparing against a placebo, which means there will be fewer subjects on the experimental drug to potentially be at risk of side effects. Finally, surrogate measures of efficacy, such as MRI measures, are being explored for phase 2 trials, but phase 3 trials will still need to use clinical endpoints as their primary outcome measures.

Exploring the potential of autologous mesenchymal stem cell transplantation as a treatment for inflammatory forms of multiple sclerosis
M. Freedman, A. Uccelli on behalf of the International MSCT Study Group

The MSCT study group recently met to come up with a strategy for conducting MS trials of mesenchymal stem cell transplantation, a technique that has shown some promise in early studies but needs to be tested further. This strategy includes phase 1/phase 2 studies conducted at multiple sites for proof of principle. There would be around 30 subjects per site, each with evidence of inflammation (relapses or enhancing lesions) despite existing therapy, and EDSS between 3.0 and 6.5. A standardized cell culture protocol would be used across all sites. Cells would be administered via IV, although the Israeli group pioneering this technique would continue its safety analysis of intrathecal administration. There would be a control group who would also receive the treatment but on a six-month delayed basis. MRI measures would be the primary outcome of these preliminary trials.

Effect of disease-modifying therapies on cortical lesions in multiple sclerosis. A comparison study
M. Calabrese, V. Bernardi, M. Atzori, I. Mattisi, A. Favaretto, F. Rinaldi, L. Rinaldi, P. Grossi, P. Perini, P. Gallo (Padua, IT)

MRI techniques that can detect cortical (gray matter) lesions have only recently been developed but could be a highly useful component in the evaluation of treatment efficacy. This study used double inversion recovery MRI (which can detect ~20% of cortical lesions) in 140 RRMS subjects who were on Copaxone, IFN-beta, or no disease-modifying therapy. MRIs were taken at baseline, 12 months, and 24 months. The treated group had fewer new cortical lesions as well as fewer white matter lesions compared with the untreated group. There was a trend towards Rebif being more effective than Copaxone which was in turn more effective than Avonex in terms of cortical lesion prevention, but this was not statistically significant.

An audience member was interested in whether the number of new white matter and gray matter lesions correlated with each other or not in individual subjects -- if not, it might mean that white and gray matter lesions were caused by different mechanisms. Dr. Gallo responded that these measures did correlate in untreated subjects, so perhaps the mechanisms behind both types of lesions are not that different.

Monthly cycles of methylprednisolone in combination with interferon beta-1a IM are efficacious in the treatment of early relapsing-remitting multiple sclerosis. The MECOMBIN study
M. Ravnborg, P.S. Sørensen, M. Andersson, E. Gulowsen Celius, P. Jongen, E. Bartholomé, I. Elovaara, K. Beer, C. Constantinescu on behalf of the MECOMBIN Steering Committee

This presentation described a trial of interferon beta plus oral methylpredisolone (MP) at 500 mg/day for 3 days per month. 172 early RRMS subjects were put on the combination and 169 were given IFN-b plus a placebo; there were many drop-outs over the course of the study. At the end of three years, no difference was seen in time to sustained progression. However, the MP group scored better on the 9 hole peg test (but not the 25 foot timed walk or the PASAT), scored better on the Integrated Disability Status Score and MS Impairment Scale, and had fewer relapses. No differences were seen in brain volume/atrophy, but the MP group did have fewer new lesions and lower lesion volume. The presenters concluded that the combination is more effective than IFN-b alone.

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Poster Sessions

I confess that I did not spend much time at the Thursday poster session -- perhaps jet lag was affecting my ability to concentrate on detailed scientific information in a crowded environment. I did notice that Robert Zivadinov's poster on chronic cerebrospinal venous insufficiency (CCSVI) had a big crowd. There seems to be growing interest in this theory that insufficient blood drainage from the brain plays a role in MS. It will be interesting to see where it leads. I also noticed a couple of posters from the MSBase Registry -- an online system where neurologists who treat people with MS can upload and store their clinical data, so that multiple centers' data can be combined for the purpose of doing really large data-driven studies. The system is now up to over 10,700 case records! One poster reported that CSF analysis and visual evoked response testing are no longer in vogue as standard MS diagnostic procedures. The other found that relapses were most common in early spring and least common in autumn, in both the northern and southern hemispheres.

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Hot Topics in MS 2: New technologies

In vivo imaging of axon dynamics in the diseased CNS
T. Misgeld (Munich, DE)

This presentation also dealt with the whizzy in vivo imaging mentioned above enabled by fluorescent labeling of axons and immune cells in mice. Examples were shown of macrophages coming into the vicinity of axons, and the resulting swelling of the axons followed by either recovery or degeneration. Mitochondrial abnormalities were detected in these axons, even before swelling occurred. A group of ions/molecules called reactive oxygen species (ROS) that are released by macrophages appear to be involved in this process. When ROS scavengers were introduced into the mice, the axons were much more likely to recover than to degenerate.

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Hot Topics in MS 1: B cells and antibodies in MS

Antibodies targeting myelin: biomarkers and more
G.P. Owens (Denver, US)

Much is still not understood about the role of B cells and antibodies in the central nervous system in MS, including what antigens the antibodies that are present are targeting. A recent study generated 73 recombinant antibodies from cells taken from the spinal fluid of 10 MS subjects. These antibodies were exposed to cells expressing myelin antigens (MBP, PLP and MOG) but did not bind to them. Nor did they appear to recognize MS brain antigens or purified myelin proteins. A subset of the antibodies did bind to fetal astrocyte cells, however. Another interesting avenue of analysis has to do with the genes encoding the antibodies found in the MS CNS. Studies have found that 70% of MS CSF plasma cells are of type VH4, and CIS subjects with a VH4 bias are more likely to progress to MS. So, progress is being made in understanding the role of CNS antibodies although the meaning of the information being produced still needs to be determined.

That was it for the day, aside from a couple of industry symposia about the benefits of certain drugs or initiating treatment early in patients. I left to meet Jacinta Behne from the Guthy-Jackson Charitable Foundation for a very enjoyable dinner at a traditional German restaurant.

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Friday September 11, 2009

The day started with a breakfast meeting with MS researcher Gavin Giovannoni to gather input for our repository strategy and discuss an interesting research idea he is developing.

Plenary Session 2: Charcot Award Lecture

The pathogenesis of relapsing and remitting multiple sclerosis – versions one to five and counting
J. Prineas (Sydney, AU)

Dr. Prineas received this year's Charcot Award for his contributions to understanding the pathology of MS, based in particular on his extensive analysis of MS tissue. In his talk, he divided the historical conception of MS into five phases (actually, he added a sixth new one at the end):

• Charcot's era: MS is a disease of the myelin involving excess glial tissue that compresses and compacts myelin, leaving the axons intact.
• 1870-1916: Myelin destruction in MS occurs acutely and begins around blood vessels.
• 1950-1960: There are other diseases of the central and peripheral nervous system characterized by perivascular demyelination (such as EAE and Guillain-Barre).
• 1960-1985: Myelin destruction in MS and EAE is caused by macrophages; he showed some neat pictures of macrophages squeezing their way into the outer layer of myelin around an axon. Remyelination can occur within a couple of weeks, indicating that the environment is no longer hostile to oligodendrocytes.
• 2004: The myelin targeted by macrophages in MS may not be normal myelin -- rather, it displays markers that attract macrophages to destroy it. He has seen lesions with apoptotic ("suicidal") oligos outside the lesion, and myelin breakdown inside the lesion with no oligo cell bodies to be found. Lesions characterized by apoptotic oligos have few lymphocytes. In newly developing lesions, he views three zones: (1) outer zone with some apoptotic cells and activated microglia but no macrophages, (2) a phagocytic zone with macrophages, (3) a post-phagocytic zone with loss of myelin and higher number of T cells and plasma cells than in the other two zones. He does not know why the oligos become apoptotic and whether the activated microglia are a cause or an effect of that.
• He believes that neuromyelitis optica (NMO), which appears to be a disease of astrocytes, is the demyelinating disease that most closely resembles MS. In NMO, there is an even deposition of complement C9 neo along the glial limiting membrane outside the blood vessel, then there is a gathering of macrophages. Astrocytes are destroyed (they may come back but are abnormal), and myelin loss happens after the loss of astrocytes. Apoptotic oligos have been seen in NMO lesions too. In MS, the connection of astrocyte "foot processes" with the glial limiting membrane is often gone (these foot processes form part of the blood-brain barrier and are a prominent target in NMO). He feels that NMO and MS are so alike that they must have something in common -- perhaps MS is also a disease of astrocytes?

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Parallel Session 8: Advances in therapy II

Cytotoxic drugs
P. Vermersch (Lille, FR)

There are three ways of using cytotoxic drugs in MS: as escalation therapies, induction therapies, or combination therapies. Escalation therapies are used when the standard drugs aren't working so you have to go to something stronger. Mitoxantrone is commonly used for this purpose, and it can reduce relapse rate and stabilize progression, although it confers risks of cardiotoxicity and leukemia. Methotrexate is often prescribed on a "compassionate use" basis when nothing else works. It is relatively safe and might reduce progression rate. Cyclophosphamide and cladribine have also been used for escalation purposes. An induction therapy is used before initiating a standard drug -- e.g., using mitoxantrone before initiating use of IFN-b or glatiramer acetate. Some combination therapies have been investigated, for instance Avonex and methotrexate, but so far there is no evidence to recommend the approach.

Monoclonal antibodies
H.-P. Hartung (Düsseldorf, DE)

Dr. Hartung reviewed some of the antibody-based MS drugs and mentioned that new data from the CAMMS223 (alemtuzumab) trial is showing a continuation of reduced relapse rate in people receiving the drug. By the way, have you ever wondered about those all drug names ending in -mab? The -mab suffixes actually have a meaning: -momab = mouse antibody; -ximab = chimeric antibody (mouse/human mix); -zumab = humanized antibody (mouse/human mix with more human, less mouse); and -umab = human-only antibody. (I never knew that!)

Oral agents
G. Comi (Milan, IT)

This was another review, although Dr. Comi did refer to a poster displaying new study data from a combination teriflunomide/IFN-b trial reporting reduction of lesions after 24 weeks.

Safety and tolerability of cladribine tablets in relapsing-remitting multiple sclerosis during the 96-week, phase III, double-blind, placebo-controlled CLARITY study
S. Cook, P. Vermersch, G. Comi, G. Giovannoni, K. Rammohan, P. Rieckmann, P.S. Sørensen, P. Chang, A. Hamlett, B. Musch, V. Viglietta, S. Greenberg (Newark, US; Lille, FR; Milan, IT; London, UK; Columbus, US; Vancouver, CA; Copenhagen, DK; Geneva, CH)

This presentation gave a more in-depth review of the safety data from the CLARITY study which was first reported at the 2009 AAN meeting. The drug (oral cladribine) met the primary and secondary endpoints. Around 90% of the subjects completed the study with similar percentages across the high-dose, low-dose and placebo groups. Treatment-emergent adverse events occurred in 73% of the placebo group vs. 82% of the cladribine subjects. There were three malignancies in the high-dose group -- Dr. Cook said that was similar to what would be expected in a cohort this size normally. There were two deaths per group (six total). An extension study which will follow these subjects for up to four more years and a treatment registry are currently being put into place.

Oral fingolimod (FTY720) significantly reduced MRI inflammatory activity compared with intramuscular interferon beta-1a in relapsing-remitting multiple sclerosis: MRI findings from a 12-month phase III study (TRANSFORMS)
F. Barkhof, J. Cohen, G. Comi, J. Pelletier, L. Kappos, H.-P. Hartung, X. Montalban, B. Khatri, P. Gallo, R. Capra, J. Jin, T. Stites, S. Wu for the TRANSFORMS (TRial Assessing injectable interferoN vS FTY720 Oral in RRMS) Study Group

The TRANSFORMS study found that two dosing levels of FTY720 each reduced annual relapse rate compared with IFN-b. This presentation reviewed the MRI data that also showed superiority of FTY720 over IFN-b in terms of new/enlarging T2 lesions, number of enhancing lesions, and brain volume change.

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Parallel Session 10: Neuroprotection and repair

Endogenous repair in the CNS
C. Lubetzki (Paris, FR)

Dr. Lubetzki reviewed several reasons why remyelination in MS is extensive but often ineffective. There could be a defect in activation, recruitment, or migration of oligo precursor cells. For instance, guidance cues such as semaphorin 3A and 3F could be dysregulated. Alternatively, maturation and myelin wrapping could be inhibited by different factors including Lingo1 and the Notch/Jagged pathway.

Axonal regeneration
R. Nitsch (Berlin, DE)

Immune cells, while posing a threat of harm to the central nervous system, also express factors that help with neuroregeneration. One example is IL-4, which is expressed by T cells and which has been shown in lab studies to stimulate regeneration of axons via their IL-4 receptors. Studies of mice whose spinal cords have been injured have demonstrated improved neurological outcomes when T cells expressing IL-4 are in the vicinity of the injury.

Regenerative therapy of experimental autoimmune encephalomyelitis by neurotrophin-3 transduced ES cell derived microglial cells
V. Lenerz, C. Beutner, R. Masgutov, S. Litwak, O. Chechneva, A. Dann, M. Prinz, H. Neumann (Bonn, Freiburg, DE)

This study explored the neuroregenerative potential of a protein called neurotrophin-3 (NT3). Mouse embryonic stem cells that were genetically engineered to express NT3 were induced to develop into microglia, and then were transplanted via IV into EAE mice at the peak of their disease. These microglia migrated into the spinal cord. In the transplanted mice compared with control EAE mice, clinical outcome was improved, axonal injury was reduced, the cytokine profile was less inflammatory, and there was more neurite growth (neuron extensions).

Genetic determinants of CNS repair following chronic demyelination in mice
K. Suwansrinon, M. Rodriguez, A. Bieber (Rochester, US)

Exposing mice to Theiler's murine encephalomyelitis virus (TMEV) results in central nervous system demyelination, making this disease one of the MS animal models. Remyelination following the demyelination occurs to different degrees depending on the strain of mouse. A research team decided to cross-breed and genetically analyze the mice to see which genes appear to affect degree of remyelination. Two genes that appear to be associated with remyelination are epidermal growth factor (EGF) (a cell development protein) and Tyk2, which is involved in the Th1 immune response. It may be that these genes also influence remyelination in humans and therefore this research could eventually lead to therapies for MS repair.

I had to skip the last talk in this session to go stand by my poster on our MS repository. Several people stopped by to see, including existing users of the repository and some people who may be in need of samples for their research in the future. The poster session was an hour and a half long, but the time passed very quickly!

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Hot Topics in MS 6: Energy metabolism

Energy metabolism in de- and remyelination
S. Komoly (Pecs, HU)

Here's a fun fact: during the myelination process, an oligodendrocyte can create up to three times its own weight in myelin each day. This requires a lot of cellular energy. In the cuprizone model of demyelination in mice, scientists have seen apoptotic oligos which have giant mitochondria. Mitochondrial DNA (mtDNA) is damaged which causes dysfunction in the energy generation system (excess PARP, insufficient ATP) which leads to cell death. Inhibiting PARP in this model can reduce the effects of the disease. Are there PARP inhibitors that could help with human MS? Minocycline is one therapy that is known to inhibit PARP, and a small study in MS showed reduction of enhancing lesions. Another PARP inhibitor called 4HQ may also be worth exploring in MS.

Role of mitochondria in MS
D. Mahad (Newcastle-upon-Tyne, UK)

This study explored the role of mitochondria in MS by looking at human brain tissue samples. Differences in certain types of mitochondrial activity (called complex I and IV) have been detected in MS brain tissue compared with controls. In addition, increased mtDNA copy numbers have been found in MS. Comparison of general brain tissue samples between MS cases and controls revealed only a slight increase in mtDNA deletions in the MS cases. However, when only single cells (neurons) were analyzed, many more deletions were found in the MS samples. In fact, many MS neurons met the 50% mutation threshold for energy dysfunction. These dysfunctional neurons seem to accumulate in MS over time. The investigators ruled out this as a simple result of the aging process since very few of these mutations are seen in controls, even older ones.

Assessing neuronal metabolism by MRI
D. Arnold (Montreal, CA)

The molecule N-acetyl-aspartate (NAA) is specifically generated by neuronal mitochondria, so declines in NAA levels are a marker of neuronal mitochondrial dysfunction. Levels of NAA and other metabolites can be measured by a special imaging technology called MR spectroscopy (MRS). Ratios of phosphocreatine to ATP decrease in MS during relapses and rebound a bit during remission. NAA levels also decrease during severe relapses and in acute lesions; this decrease is also partially reversible. Interestingly, NAA in normal appearing white matter initially decreases in MS but then stabilizes. A study of glatiramer acetate in CIS subjects showed that the therapy appeared to increase NAA levels (levels declined in subjects receiving placebo). Perhaps Copaxone helps to reverse mitochondrial dysfunction?

Friday night featured a lively group dinner organized by Jacinta Behne of the Guthy-Jackson Foundation at a restaurant near the convention center.

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Saturday September 12, 2009

Last day of the conference!

Parallel Session 13: Late breaking news

Abundant alterations in microRNA and mRNA target expression in grey and white matter lesions of patients with multiple sclerosis
B.A. de Jong, M.H. Han, E.J. Kooi, R.A. Sobel, J. Geurts, C.H. Polman, L. Steinman (Stanford, US; Amsterdam, NL)

Messenger RNA (mRNA) molecules are snippets of copied DNA that are translated into chains of amino acids to make proteins. Micro RNA (miRNA) are also snippets of copied DNA that do not get translated into proteins but instead regulate protein production by targeting specific mRNAs to keep them from being translated. A research team analyzed gray matter and white matter from 5 MS cases and 5 controls for miRNA and mRNA. They found many miRNAs and mRNAs that were differently expressed in cases vs. controls. Focusing on the miRNAs, those that were differently expressed often targeted mRNAs involved with myelin formation, nerve growth, synapse functioning, ion channels, and inflammation. Dr. de Jong focused on one of these, mTOR, which is targeted by the drug rapamycin. Rapamycin modulates the immune system by encouraging a shift to T regulatory cells, and has been shown to delay EAE onset.

MxA mRNA level predicts relapses in a prospective cohort of early MS patients
L.F. van der Voort, A. Vennegoor, A. Visser, D.L. Knol, B.M. Uitdehaag, F. Barkhof, C.B.M. Oudejans, C.H. Polman, J. Killestein (Amsterdam, NL)

Myxovirus resistance protein A (MxA) is a biomarker for response to IFN-b, so a research team decided to investigate whether it would also be a biomarker for other aspects of MS. They measured MxA mRNA in 67 CIS subjects, 49 MS subjects, and a group of controls. MxA mRNA was highest in controls, next highest in CIS/MS subjects in remission, and lowest in subjects having a relapse. Low MxA mRNA was also associated with a shorter time to the next relapse. However, MxA mRNA did not correlate with MRI developments over the next two years.

Trial period for new symptomatic treatments: lessons learnt from a Sativex in MS spasticity clinical trial
X. Montalbán, S. Wright (Barcelona, ES; Salisbury, UK)

A new twist on drug trial study design was used to evaluate the cannabinoid drug Sativex as an MS spasticity treatment. Rather than dividing the study cohort into a treatment arm and a placebo arm, the investigators put the entire cohort on treatment for four weeks. Those who appeared to respond (by having a 20% or higher reduction in spasticity) were then randomized to placebo or further treatment for 12 weeks. This design was chosen because the investigators knew from past trials that only a subset of the participants would respond, so narrowing the group down after four weeks would save money and prevent some unnecessary side effects. At the end of the 12 weeks, 74% of those on Sativex had achieved a spasticity reduction of at least 30%. 47% experienced some adverse effects and 5% of the participants dropped out because of these effects (dizziness, fatigue, etc.). The investigators recommended that a four-week trial period of Sativex use might be a good practice for determining whether someone with MS-related spasticity would benefit from it.

Atorvastatin therapy in patients with clinically isolated syndrome and high-risk for conversion to multiple sclerosis: the STAyCIS study
E. Waubant, D. Pelletier, M. Mass, J. Cohen, M. Kita, A. Cross, A. Bar-Or, T. Vollmer, M. Racke, O. Stüve, S. Schwid, A.D. Goodman, N. Kachuck, J. Preiningerova, B. Weinstock-Guttman, P. Calabresi, A. Miller, M. Mokhtarani, L. Ding, E. Rosenberg, . ITN020AI Study Management Team, D. Iklé, C. Spencer, S.S. Zamvil (San Francisco, Portland, Cleveland, Seattle, St. Louis, US; Montreal, CA; Phoenix, Dallas, Rochester, Los Angeles, New Haven, Buffalo, Baltimore, New York, Bethesda, Chapel Hill, US)

The STAyCIS trial compared the efficacy of 80 mg of atorvastatin vs. placebo in people with CIS. Unfortunately, recruitment was very slow so the study team decided to stop enrollment after only 82 subjects. The primary outcome was development of three new T2 lesions or a clinical exacerbation. This outcome was met in fewer treatment subjects than placebo subjects (49% vs. 56%); however, this difference was not statistically significant. One bright note was that treated subjects were much more likely not to have any new lesions in the first 12 months. 18% of the treated subjects (vs. 12% of placebo subjects) had adverse effects leading to drop-out; 24% of the treated subjects (vs. 3% of placebo subjects) had adverse effects leading to a decrease in dose. Statin-related adverse effects included nausea and elevated ALT and AST levels.

A double-blind, placebo-controlled, multi-centre study to evaluate the efficacy and safety of dirucotide in patients with secondary progressive multiple sclerosis
M. Freedman, T. Verco, M. Ossanna, M. Nilsson, L. Ferenczi, A. Chappell, D. Lin, L. Arfors, M. Krantz (Ottawa, Edmonton, CA; Indianapolis, US)

Dirucotide is an IV-administered drug that is a synthetic peptide matching a particular myelin basic protein (MBP) sequence. An earlier study suggested that it could be effective in treating secondary progressive MS in people with HLA DR2 or DR4 genetic haplotypes. The current study was placebo-controlled and designed to last 24 months with a possible extension phase. The primary outcome was progression of one point on the EDSS sustained for six months. Unfortunately, the trial did not demonstrate efficacy of this drug in terms of progression. In addition, no impact was seen on T2 burden of disease.

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Plenary Session 3: Pathology and ECTRIMS highlights

Neuromyelitis optica – new insights into pathogenesis
H. Lassmann (Vienna, AT)

Dr. Lassmann reviewed what we currently know about the pathology of NMO. The discovery of anti-aquaporin 4 (AQP4) antibodies in people with NMO has been a key development in the understanding of this disease. Tests have now shown that these antibodies are actually harmful (as opposed to just being a disease marker). In vitro studies show that anti-AQP4 can kill astrocytes directly and can downregulate AQP4 and another protein (EAAT-2). Mice with EAE get NMO-like lesions when they are injected with these antibodies (these lesions are not seen when MS or control serum is injected). However, the presence of these antibodies is not enough to cause disease. High titers are not always associated with a relapse, and some people have anti-AQP4 years before their first symptom. When you inject AQP4 antibodies into normal rats, there is no effect, so probably something else is needed to cause a breakdown in the blood-brain barrier. Dr. Lassmann's lab is exploring the role of inflammation in NMO. When they inject AQP-4 reactive T cells into mice, there is no clinical disease although there is lots of inflammation and upregulation of AQP4. However, when both these T cells and anti-AQP4 antibodies are transferred, NMO-like lesions develop.

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The conference was over around noon, so I took the opportunity to visit the cathedral in Cologne, did a little shopping for the folks back home, and finished the day with dinner at an Irish pub in the Altstadt. The next morning I said "auf wiedersehen" to Dusseldorf and caught a flight back to Boston.

My impression of this conference was that it is clear that steady progress continues to be made in many areas, although there were few truly stand-out presentations. However, the level of attention being devoted to NMO has definitely gone up from recent years. This is due to the discovery of the anti-AQP4 antibody which gives scientists a lever to use in learning more about the disease. Hopefully this lever will lead quickly to new therapeutic options for this often severe and disabling condition.