ACTRIMS + ECTRIMS + LACTRIMS

If it's on your mind and it has to do with multiple sclerosis in any way, post it here.

ACTRIMS + ECTRIMS + LACTRIMS

Postby dignan » Thu Sep 18, 2008 12:33 pm

The ACTRIMS + ECTRIMS + LACTRIMS conference is on, as many of you know. For my money, the presentations at this event are the most interesting of any conference over the last 5 years. Below are a whole lotta abstracts from today (so the embargo is off) that I find interesting. If you want to see more, go to:

http://msmontreal.abstractcentral.com/login – then select “Browse” from left-hand menu.
(thank you Bromley for the link)

Neurodegeneration and inflammation: which comes first?

Evidence for primary neurodegeneration in multiple sclerosis
W. Brück
Neuropathology, University Medical Centre, Göttingen, Germany.
Multiple sclerosis (MS) is generally regarded as an inflammatory demyelinating disease of the central nervous system. There is increasing evidence that MS also has a neurodegenerative component which appears to be the major cause of disability of MS patients. One of the major questions in MS pathogenesis is whether this neurodegenerative component occurs as a consequence of early inflammatory demyelination specifically in the progressive disease stage or whether neurodegeneration is an early phenomenon in MS lesions. There is increasing evidence from morphological studies that axonal pathology such as axonal transections or acute axonal damage occurs early in MS lesions but also in areas that are described as normal appearing white matter. This is supported by recent magnetic resonance imaging (MRI) and magnetic resonance spectroscopic (MRS) studies. In addition, cortical pathology with demyelination and neuroaxonal damage also appears to be an early event in lesion pathogenesis and contributes to the permanent clinical deficit of the patients. The presentation will give an overview on the current knowledge and evidence for primary neurodegenerative events in the pathogenesis of MS lesions.


Evidence for secondary neurodegeneration in multiple sclerosis
W. Moore
Pathology and Laboratory Medicine, University of British Columbia, Vancouver General Hospital, Vancouver , BC, Canada.
Neuropathological studies of multiple sclerosis (MS) have shown reduced numbers of axons in normal-appearing white matter (NAWM) attributed to Wallerian degeneration of axons within white matter plaques. This is also manifest as tractal degeneration in MS spinal cord.

Inflammatory cells in close proximity to degenerating axons in MS are considered to be mediators of axonal destruction. Components of the immune/inflammatory response, shown to have detrimental morphologic or physiologic effects on neurons/axons, have been documented by immunohistochemistry or molecular biological techniques in the MS plaque. These include CD4 lymphocytes and their proinflammatory and immunomodulatory cytokines, CD8 cytotoxic T-cells, activated microglia, macrophages (with proteases and other enzymes), matrix metalloproteinases, chemokines, anti-neuronal antibodies, complement, calpains, glutamate, cyclooxygenase-2, nitric oxide (NO), peroxynitrite and free radicals. NO is particularly toxic to demyelinated axons. Inflammation has also been detected in NAWM, where similar neurodegenerative factors may be operative. Degeneration of neuronal somata and neurites has been attributed to the effects of activated microglia in gray matter.

Blood–brain barrier dysfunction in MS plaques and NAWM, secondary to the inflammatory infiltrates, allows the introduction of previously-excluded systemic neurotoxins into the CNS parenchyma.

Demyelination itself is associated with secondary changes in axons, including dephosphorylation of neurofilaments and reduction in axonal diameter.

The redistribution of sodium channels along the demyelinated axolemma, evident in immunohistochemical studies, results in excessive energy demands on the axon and increased axoplasmic sodium concentration, the latter triggering the sodium–calcium exchanger leading to toxic levels of intra-axonal calcium. The insertion of calcium channels in the demyelinated axolemma has a similar effect.

In summary, histopathologic, immunohistochemical and molecular studies of plaques and non-plaque parenchyma indicate that neurodegeneration in MS may be secondary to the effects inflammation and demyelination.


Brain plasticity and repair

Mesenchymal stem cells as treatment for multiple sclerosis: immunomodulation versus tissue repair
A. Uccelli 1; S. Morando1; M. Esposito2; M. Principato1; D. Giunti1; S. Chiesa1; G. Martino2; G. Mancardi1; R. Furlan2
1. Neuroscience, Ophthalmology and Genetic, University of Genoa, Genoa, Italy.
2. San Raffaele Hospital, Milan, Italy.
While bone marrow derived mesenchymal stem cells (MSC) have been proposed for brain repair due to their multipotentiality, recent experimental data challenged their transdifferentiation capacity and suggested that they could modulate pathogenic immune responses.

The aim of this study was to address the in vivo effects of MSC on neural cells inside the inflamed central nervous system (CNS) as well as on key T cell subsets infiltrating both in the lymphoid organs and in the CNS.

We evaluated the MSC-mediated effects in MOG-induced experimental autoimmune encephalomyelitis (EAE) by immunological, histological and molecular analysis of CNS specimens.

We showed that irrespective of the lack of MSC neural differentiation, MSC decreased axonal sufferance through the inhibition of astrogliosis and microglia activation and the upregulation of genes involved in the BMP and Notch pathways. In addition, upon isolation of T cells from the brain of EAE-affected mice we detected an increase of CD4+ FoxP3 + T regulatory cells and a decrease of IL-17 producing T cells compared with control EAE mice.

Thus MSC may represent a valuable approach for the treatment of autoimmune diseases such as multiple sclerosis where tissue degeneration is associated with inflammation.


Antibodies: from pathogenesis to treatment

Monoclonal antibodies: the future
S. L. Hauser1
1. Neurology, University of California, San Francisco, San Francisco, CA, USA.
In contrast to earlier disease concepts of MS suggesting that pathogenic T cells were sufficient for full expression of the disease, it is now established that autoimmune B cells and humoral immune mechanisms also play major roles in mediating tissue damage. Current evidence indicates that diverse protein and lipid antigens are likely to be targets of humoral autoimmunity in MS.

In MS, memory B cells, which cross the blood-brain barrier, are believed to undergo restimulation, antigen-driven affinity maturation, clonal expansion, and differentiation to antibody-secreting plasma cells within the highly supportive CNS environment. Clonally expanded populations of memory B cells and plasma cells are also present in MS lesions and in cerebrospinal fluid, and can be detected even at the onset of clinical symptoms.

In a phase II trial in RRMS reported in 2007, Rituximab (Rituxan), a chimeric monoclonal antibody that targets CD20-positive B lymphocytes, reduced disease activity measured by MRI; secondary endpoints were also positive, including a reduction of clinical relapses. Suggestive efficacy was also observed in a phase 1 trial. In primary progressive MS, a phase II/III trial has been completed and preliminary results will be presented at this meeting.

The beneficial effects in the RRMS anti-CD20 trials occurred within weeks of the initial infusion, indicating that a direct effect on B cells - and not on autoantibodies – was responsible. Interference with B cell trafficking is one presumptive mechanism of action. The duration of action was also longer than the period of B cell depletion, suggesting that repopulating B-cells were less pathogenic. In a larger sense, the discovery that B-cell depletion has an impact on MS biology represents a paradigm shift in understanding how the inflammatory phase of MS develops; the data shift our perspective on the cause of MS, and open up a new area of investigation which may lead to development of increasingly selective therapies against humoral immune system pathways.


Poster Sessions

A Phase I/II dose-escalation trial of oral vitamin D3 with calcium supplementation in patients with multiple sclerosis
J. M. Burton1; S. Kimball2; R. Vieth2; A. Bar-Or3; H. Dosch4; L. Thibault5; S. Kilborn5; C. D'Souza6; R. Cheung4; M. Ursell7; P. O'Connor1
1. St. Michael's Hospital, Toronto, ON, Canada., 2. Mount Sinai Hospital, Toronto, ON, Canada., 3. Montreal Neurological Institute, Montreal, QC, Canada., 4. Hospital for Sick Children, Toronto, ON, Canada., 5. McGill University, Montreal, QC, Canada., 6. University of Toronto, Toronto, ON, Canada., 7. Etobicoke General Hospital, Etobicoke, ON, Canada.
Increasing distance from the equator, low UV radiation and low serum 25-hydroxyvitamin D [25(OH)D] are associated with increased multiple sclerosis (MS) prevalence and risk. While this relationship provides insight into prevention, it begs the question, ‘Is vitamin D3 (VD3), known to have immunoregulatory properties, beneficial in established MS?’ To answer this, a safe, effective dose must be determined.

To characterize the safety profile of high-dose oral VD3 in MS.

A prospective controlled 52-week trial matched MS patients for demographic and disease characteristics, randomizing them to treatment or control groups. Treatment patients started VD3 at 4000 IU/day and escalated over 28 weeks to 40 000 IU/day. This was followed by maintenance with 10 000 IU/day for 12 weeks, 4000 IU/day for 8 weeks and a 4-week wash-out, translating into roughly 14 000 IU/day over 52 weeks. Calcium (1200mg/day) was given throughout the trial. The primary endpoint was mean change in serum calcium in treatment patients at each VD3 dose, and a comparison of calcium between treatment and control groups. Secondary endpoints included 25(OH)D, urine calcium/creatinine (Ca/Cr) and PTH. Cytokines, lymphocyte response and matrix metalloproteinase-9 were also measured, as were Expanded Disability Status Scale (EDSS) and relapses.

Forty-nine patients were enrolled (25 treatment, 24 control) with mean age 40.5 years (21–54 years), EDSS 1.34 (0-6.0) and 25(OH)D 78nmol/l (38–154). No abnormalities or differences in serum calcium, urine Ca/Cr or PTH occurred, nor were there differences in calcium between groups. Despite a maximum mean 25(OH)D of 413nmol/l (66–729), no significant clinical or biochemical adverse events occurred. A greater proportion of treatment patients had stable/improved EDSS vs. control patients (p=0.018). Treatment patients also had fewer relapses and a greater reduction in relapse rate vs. controls. Immunological data will be presented.

High-dose VD3 (~10 000 IU/day, possibly higher) in MS is safe and tolerable, with evidence of clinical improvement.


Association of interferon beta and inosine in relapsing–remitting multiple sclerosis (ASIIMS): a multi-centre, randomized, double-blind, placebo-controlled phase II (proof of concept) trial in 157 patients
R. E. Gonsette1; C. Sindic2; M. D'Hooghe3; R. Medaer4; A. Michotte5; P. De Deyn6; P. Seeldrayers7; D. Guillaume8; R. Metz9; A. Maertens de Noordhout10; M. Dupuis11; P. Cras12; D. Decoo13; M. Van Zandijcke14
1. National Centre for Multiple Sclerosis, Melsbroek, Belgium., 2. UCL, Brussels, Belgium., 3. NCMS, Melsbroek, Belgium., 4. LUC, Dieprnbeek, Belgium., 5. VUB, Brussels, Belgium., 6. AZ Middelheim, Antwerp, Belgium., 7. CHU, Charleroi, Belgium., 8. CNRF, Fraiture, Belgium., 9. CH, Luxembourg, Luxembourg., 10. CHU, Liège, Belgium., 11. Clinique St-Pierre, Ottignies, Belgium., 12. UZ, Antwerp, Belgium., 13. EZ, Sijsele, Belgium., 14. AZ, Brugge, Belgium.
Neuronal and axonal loss occurs early in relapsing–remitting multiple sclerosis (RRMS) and is mediated by inflammatory processes as well as by oxidative stress and excitotoxicity. Effective anti-inflammatory drugs are available but the development of neuroprotective agents remains a challenge. Experimental and clinical observations suggest that uric acid (UA), a natural antioxidant, has a neuroprotective effect in EAE and possibly in MS. Oral administration of inosine, a precursor of UA, increases serum and CSF UA levels in MS patients and is well tolerated.

Combination therapy with an anti-inflammatory drug (IFNβ) and a potentially neuroprotective agent (inosine) might delay disability progression.

Patients with RRMS who had been on IFNβ for at least 6 months at baseline were randomized to IFNβ + inosine (n=79) or IFNβ + placebo (n=78) for 2 years. The two groups were not significantly different in terms of age (~37 years), disease duration (~6.2 years), mean EDSS (~2.3) and annual relapse rate (~0.8). The dose of inosine was adjusted to maintain serum UA levels in the range of asymptomatic hyperuricemia (females ≤8mg/dL; males ≤9mg/dL). Expanded Disability Status Scale (EDSS) and MSFC components were assessed every 3 months by a blinded evaluating physician. The primary end points were: percentage of patients with progression of disability (EDSS+1 confirmed at 3 months), time to sustained progression (Kaplan–Meier analysis) and mean EDSS.

The combination of IFNβ and inosine was safe and well tolerated. Urinary lithiasis occurred in 3.8% of treated patients and 1.3% of controls. No change in blood pressure was noted in patients with induced asymptomatic hyperuricemia. At 24 months no significant differences were observed between the two groups in any of the primary end points.

Combination therapy with IFNβ and inosine is not superior to IFNβ monotherapy. Potential reasons will be discussed. Inosine effects might be masked by those of IFNβ and the negative results of this combination therapy do not rule out a possible benefit of UA in naîve patients.


Treatment of multiple sclerosis with glatiramer acetate and albuterol: results of a clinical trial
P. Kivisäkk1; V. Viglietta2; B. Healy1; G. J. Buckle1; H. L. Weiner1; D. A. Hafler1; S. Khoury1
1. Brigham and Women's Hospital, Boston, MA, USA., 2. EMD Serono, Boston, MA, USA.
The mechanism of action of glatiramer acetate (GA) is thought to be by induction of anergy of GA reactive lines and enhanced production of Th2 cytokines. We hypothesized that albuterol may enhance the effects of GA in vivo or accelerate the induction of anergy and Th2 cytokine production.

In a randomized, double-masked, two-arm pilot study we investigated the effect of adding oral albuterol versus placebo to GA in relapsing–remitting multiple sclerosis (RRMS).

Eligibility criteria were clinically definite RRMS with positive brain magnetic resonance imaging (MRI), and an Expanded Disability Status Scale (EDSS) score between 0 and 3.5. No prior treatment with GA or oral myelin. No treatment with immunomodulating therapy within the past 3 months. No prior treatment with immunosuppressants. No steroid treatment 1 month prior to study entry. Subjects were randomized to two treatment arms: 20mg SQ of GA daily + 4mg PO of placebo daily for 2 years or 20mg SQ of GA daily + 4mg PO of albuterol daily, for 2 years.

The primary outcome measures were the change in the MS Functional Scale (MSFC), and the change in IL-13 and IFN-γ cytokine secretion by GA reactive T cell lines. Secondary outcome variables included changes in percentage of IL-12-producing monocytes by intra-cytoplasmic staining, time of first exacerbation, number and severity of exacerbations, and MRI evidence of progression.

Forty four subjects were randomized (21 in the GA+placebo arm and 23 in the GA+albuterol arm). There was a treatment effect of albuterol on MSFC at 6 months that diminished over time (p=0.026) and a trend for improved MSFC in the albuterol arm at 12 months. Analysis of the immunologic endpoints is ongoing.

Albuterol added to GA treatment in RRMS enhanced treatment response in the early time points and may be beneficial in accelerating the beneficial effects of therapy.


Immediate broad spectrum immunomodulating effects induced by bone marrow derived stem cells (MSC), in MS patients transplanted with MSC in a phase I/II clinical trial
A. Vaknin-Dembinsky1; I. Kassis1; C. Karageorgiou2; B. Gowda-Kurkalli3; J. Rachmilewitz3; Y. Libster1; T. Ben-Hur1; S. Slavin3; D. Karussis1
1. Neurology, Hadassah-Hebrew University Hospital, Jerusalem, Israel., 2. Gennimatas General Hospital, Athens, Greece., 3. Tel Aviv (Sourasky) Medical Center, Tel Aviv, Israel.
Bone marrow (BM) mesenchymal stem cells (MSC) possess strong neurotrophic effects and have become the focus of research as a potential method for inducing neuroprotection in diseases such as multiple sclerosis (MS). MSC were also proven to exert strong in vitro immunomodulatory effects.

To evaluate the immediate immunomodulatory effects of MSC in MS patients in a phase I/II clinical trial with intravenous and intrathecal administration of MSC.

A total of 14 MS patients were injected with autologous MSC, following their culture for 40-90 days. All patients received intrathecally a mean of 64.4, and 10 of them intravenously, a mean of 22 million cells. We performed an immunological analysis in 6 of the patients before the injection of the stem cells and 4 and 24 hours later. Peripheral blood monocytes were obtained and the following tests were perfomed: a) FACS analysis for the expression of markers of regulatory cells (CD4/CD25/FoxP3), myeloid dendritic cells activation markers (CD86, CD83 and HLA-DR), T-cell activation markers (CD69), b) lymphocyte proliferations assay and c) cytokine production.

All tested patients showed significant changes in all the above immunological tests, starting as early as 4 hours following the injection of MSC, including a 30-50% increase in the proportion of CD4+CD25+ regulatory T cells and 30-60% reduction of CD83 expression on myeloid dendritic cells. In addition, in vitro a significant decrease was noted in the proliferative responses upon stimulation of the lymphocytes with anti-CD3 or the PHA mitogen as well as a significant decrease in IL-17 secretion.

This is the first trial with intrathecal and intravenous injection of MSC in MS and revealed the strong immediate immunomodulatory effects induced by the injection of these cells. Further controlled studies and longer observation periods are needed to evaluate possible efficacy and long-term clinical and immunological effects of MSC transplantation.


Epigenetic marks in the brain of patients with secondary progressive multiple sclerosis
P. Casaccia1; F. Mastronardi2
1. Neuroscience, Mount Sinai School of Medicine, New York, NY, USA., 2. Hospital for Sick Children, Toronto, ON, Canada.
The gender prevalence of multiple sclerosis (MS), the low-level concordance in homozygous twins and the linkage to several genetic loci, suggest an epigenetic component to the definition of this demyelinating disorder. Epigenetics refers to the changes in gene expression that are consequent to secondary modifications of nucleosomal histones, the basic unit of chromatin, and/or DNA methylation.

Since modification of lysine residues in the tail of nucleosomal histones associated with repression are essential for developmental myelination in rodents, we asked whether specific patterns of post-translational modifications of the histones could be identified in human MS brains compared with non-MS controls.

Protein extracts were generated from the normal appearing white matter in brain samples obtained from the UCLA MS Brain Bank. Only samples from patients with secondary progressive MS, matched by age, sex, brain region and equivalent autolysis time were analyzed and compared with brain samples from non-neurological patients. Proteins were quantified and processed for Western-blot analysis using antibodies specific for lysine residues in the histone tails.

We detected decreased levels of epigenetic marks for repression of gene expression (that is, repressive methylation of lysine 9) and decreased expression of the enzymes responsible for deacetylation of nucleosomal histones (that is, histone deacetylases).

The epigenetic marks defining the oligodendrocyte lineage progression during development are decreased in the normal appearing white matter of patients with secondary progressive MS.
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Postby dignan » Thu Sep 18, 2008 2:40 pm

Ok, that link I posted apparently doesn't work (my fault, not Ian's!), so try this one:

http://www.msmontreal.org/program/scientific_e.asp#haut

then hit the "Itinerary Planner" link, then "browse"...I hope that works, if not, I quit!
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Postby gwa » Thu Sep 18, 2008 3:11 pm

Thanks dignan! There is lots of information here and I agree that this may be the best batch of info thus far.

gwa
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Postby rainer » Thu Sep 18, 2008 4:13 pm

good stuff! it's hard for me to parse what they mean by "secondary" in the inflammation abstract "Evidence for secondary neurodegeneration in multiple sclerosis". Seems like it says damage is taking place without inflammation but then that inflammation is encouraging damage.

I didn't know there was an embargo in place. does that make ECTRIMS the cuban missile crisis?
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Postby dignan » Thu Sep 18, 2008 4:44 pm

Yes rainer, please keep your freighter clear of ECTRIMS waters...oh and also don't post abstracts until the presentation has taken place...although I don't know if the embargo applies to us since we're not media...
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Postby dignan » Fri Sep 19, 2008 9:47 pm

Well after that punch in the gut from the good folks at Opexa, maybe some more good news is required, so here are my favorite Friday abstracts from the conference:


Emerging therapies

Treatments that target macrophages and microglia
S. Khoury
Brigham and Women's Hospital, Boston, MA, USA.

Macrophages and activated microglia cells are the key effectors for tissue injury in inflammatory conditions of the central nervous system (CNS). Microglia share many phenotypical and functional characteristics with other tissue macrophages and with peripheral blood monocytes. Reactive microglia play a significant role in the initiation and propagation of immune responses as the inflammatory mediators during the process of inflammation in the CNS. Microglial response to extracellular stimuli is mediated by kinase and phosphatase cascades. Activated microglia are present in multiple sclerosis (MS) lesions and its animal model experimental autoimmune encephalomyelitis (EAE), where chronically activated microglia appear to impact the repair potential of neural stem cells. Treatments that target microglia activation have a positive impact on EAE. Compounds that inhibit microglia activation include glucocorticoids, minocycline, vitamins A, D, and E, chondroitin sulfate, endocannabinoids, PPAR-gamma agonists, and anti-CD200 antibodies. Several of the drugs and molecules described suppress the neurotoxic effect of microglial cells in EAE. For these targets to become viable therapeutic options for MS and other CNS diseases would require that they cross the blood-brain barrier and target functional properties of the CNS antigen-presenting cells and at the same time have limited toxicity.


Safety, phase I/II study with intrathecal and intravenous injection of mesenchymal stem cells in patients with multiple sclerosis and amyotrophic lateral sclerosis
D. Karussis1; C. Karageorgiou2; B. Gowda-Kurkalli3; A. Vaknin-Dembinsky1; I. Kassis1; G. Gkortzolidis2; H. Papageorgiou2; E. Stavropoulou2; P. Petrou1; T. Ben-Hur1; S. Slavin3
1. Neurology, Hadassah-Hebrew University Hospital, Jerusalem, Israel.
2. Gennimatas General Hospital, Athens, Greece.
3. Tel Aviv (Sourasky) Medical Center, Tel Aviv, Israel.

Neurodegenerative diseases of the central nervous system and the degenerative phase of multiple scerosis (MS) are less amenable to treatment modalities. Neuroprotective approaches for such diseases could provide a solution and are currently under investigation. Bone marrow (BM) derived mesenchymal stem cells (MSC) possess strong neurotrophic and immunomodulatory properties. They were beneficial in several experimental models of neurological diseases, and specifically were very efficient in suppression of experimental allergic encephalomyelitis, the animal model of MS. The ability to easily obtain MSC from the patient, expand them in culture and re-introduce them as an autologous graft, as well as the lack of risk for malignant transformation make these cells excellent candidates for cell therapy.
To evaluate the feasibility and safety of intrathecal administration of BM-MSC in patients with severe MS and with amyotrophic lateral sclerosis (ALS).

Thirteen MS patients with a mean EDSS score of 6.8 and 14 ALS patients with a mean ALSFRS score of 22.0 were included in this trial. Following culture of the cells for 40-90 days in a Clean Room facility (GMP), BM-MSCs were cryopreserved until sterility was confirmed after additional 14 days. All patients received intrathecally a mean of 64.4 million cells. Ten patients were injected also intravenously with MSC.
In 20 patients there were injection-related side effects of transient meningeal irritation and mild fever which lasted for 1-2 days. No major side effects were reported during a follow up period of up to 25 months. The mean ALSFRS remained stable during the 6 first months of observation (22.1-22.6), whereas the mean EDSS score improved to 6.0 and 5.7 at 3 and 6 months respectively.

This is the first trial with intrathecal injection of MSC in MS and ALS and shows the safety and feasibility of the procedure. Further controlled studies and longer observation periods are needed to evaluate possible efficacy and long term effects of this treatment.


Effects of glucosamine sulfate on multiple sclerosis progression: a randomized, placebo-controlled trial
V. Shaygannejad1; F. Ashtari1; M. Janghorbani2
1. Isfahan Neuroscience Research Center ( INRC), Isfahan, Iran.
2. Isfahan University of Medical Sciences ( IUMS), Isfahan, Iran.

Glucosamine, a natural glucose derivative and an essential component of glycoproteins and proteoglycans, has been safely used to relieve osteoarthritis, but there is no evidence to support its use in multiple sclerosis (MS).

The aim of this study was to evaluate the effectiveness of glucosamine sulfate in the prevention of progression of MS.

One hundred and twenty definite MS patients age 17 to 55 years were randomly allocated to receive a 6-month treatment course of either oral glucosamine sulfate (1500 mg/day) or placebo. Response to treatment was assessed at 6 months after start of therapy.

The results of the study demonstrated that a slight but significant improvement in relapse rate occurred in the glucosamine sulfate group. Of the 60 patients treated with glucosamine sulfate, the mean (SD) of relapse rate decreased from 1.2 (0.7) at baseline to 0.5 (0.6) at the end of the study period (P<0.01). Correspondingly, in the 60 patients treated with placebo, the mean (SD) of relapse rate did not change. After 6 months, 53.3% of patients receiving glucosamine sulfate remained relapse-free compared with 48.3% of those given placebo. The average Expanded Disability Status Scale (EDSS) score at the end of trial did not changed between glucosamine sulfate and placebo group (mean difference, 0.2; 95% CI, -0.4, 0.8).

Thus, this study suggests that treatment with glucosamine sulfate significantly reduces relapse rate in patients with MS. No significant differences were seen between glucosamine sulfate and placebo on the mean (SD) EDSS.


Monthly ambient sunlight, vitamin D, infections and relapse rates in multiple sclerosis
H. Tremlett1; I. van der Mei2; F. Pittas2; L. Blizzard2; G. Paley2; D. Mesaros2; R. Woodbaker2; M. Nunez3; T. Dwyer4; B. Taylor2; A. Ponsonby2
1. Medicine (Neurology), University of British Columbia, Vancouver, BC, Canada.
2. Menzies Research Institute, University of Tasmania, Hobart, TAS, Australia.
3. School of Geography and Environmental Science, University of Tasmania, Hobart, TAS, Australia.
4. Murdoch Childrens’ Research Institute, University of Melbourne, Melbourne, VIC, Australia.

Seasonal variation in multiple sclerosis (MS) relapses has been found in the northern hemisphere. The relationship between seasonal environmental factors, infections, serum vitamin D (25(OH)D) and MS relapses is undetermined.

To examine the relationship between seasonal environmental factors, infections, serum 25(OH)D and MS relapses in the southern hemisphere.
We prospectively followed a population-based cohort of relapsing-remitting MS (RRMS) patients in southern Tasmania (between January 2002 and April 2005). Correlations between monthly ambient environmental factors, predicted serum 25(OH)D, upper respiratory tract infections and relapse rates were examined using weighted Pearson’s correlation and linear regression.

Of 199 definite MS patients, 142 had RRMS and were followed for a mean of 2.3 years. The relapse rate exhibited a moderate peak in winter with a nadir in summer (relapse rate =1.3(95% CI: 1.0-1.8) vs. 0.9 (95% CI: 0.7-1.4) per 1000 days of follow-up). Monthly relapse rates correlated with: (1) erythemal ultraviolet radiation when lagged 1.5 months prior, r=-0.32, p=0.046; (2) upper respiratory tract infection rate (no lag), r=0.39, p=0.014; and (3) predicted serum 25(OH)D (no lag), r=-0.31, p=0.057. The association between upper respiratory tract infection rate and relapses was reduced after adjustment for monthly erythemal ultraviolet radiation.

None of the other ambient environmental factors examined (including ozone, particulate matter PM10, rainfall, temperature and sea level pressure) were significantly associated with relapses.

Relapse rates were inversely associated with ambient ultraviolet radiation, vitamin D levels and positively associated with upper respiratory tract infections. The demonstrated lag between ultraviolet radiation but not serum 25(OH)D and relapse rates is consistent with a role for ultraviolet radiation-generated vitamin D in the alteration of relapse rates. Future work on the association between upper respiratory tract infections and relapses should be considered in the context of ultraviolet radiation and vitamin D.
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Upper respiratory=sinus?

Postby lyndacarol » Sat Sep 20, 2008 7:39 am

I found this last abstract, posted by dignan, to be especially interesting because I suspect a connection with sinusitis (more specifically, mucus), as we discussed earlier in General Discussion, "MS and Sinusitus" (http://www.thisisms.com/ftopict-5131.html), and now hinted at in this abstract:
Relapse rates were inversely associated with ambient ultraviolet radiation, vitamin D levels and positively associated with upper respiratory tract infections.


I do hope someone will follow through with more research, as they wrote:
Future work on the association between upper respiratory tract infections and relapses should be considered in the context of ultraviolet radiation and vitamin D.

But so often this is said and no one does!
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Postby mrhodes40 » Sat Sep 20, 2008 11:57 am

Wow, what a great batch of findings!

I am most interested in the ones related to harvesting your own stem cells and having them reintroduced after growing in the lab for a while;
that kind of treatment once shown to be beneficial should be available at any cancer treatment center that has been treating leukemia, because that is a small part of what they do in those procedures. Hematologists will be the docs in that field.

it will be completely safe too, just like harvesting blood for yourself before you get surgery, then using it if you have blood loss on surgery day. Same thing here only selectively using the stem cells rather than all of your blood.

I liked that patients showed some delayed improvement also, my belief has been that a treatment every 6 months or something would be best vs the idea of some kind of 'one shot' rebooting somehow taking place due to this kind of therapy. Immune cells have a lifespan, so reintroducing a stabilizing therapy regularly makes sense.

I hope the fact that such things can be done at multiple facilities vs some exclusive patentable thing does not get in the way of more research!

Anyone have an idea of off label possibilities for something like that? People travel to China or Central America to do it even now at a cost of 20-40 thousand US dollars, be good if people could do it here.

I wonder what would happen if one saw a hematologist and asked for this based on these findings? :D
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Postby dignan » Sat Sep 20, 2008 5:59 pm

Last, but not least, here are my picks from the Saturday abstracts:


Late Breaking News

Results from a phase III, one-year, randomized, double-blind, parallel-group, dose-comparison study with glatiramer acetate in relapsing-remitting multiple sclerosis
G. Comi1; J. A. Cohen2; M. Filippi3
1. Department of Neurology, University Vita-Salute and Scientific Institute San Raffaele, Milan, Italy.
2. Mellen MS Center, Cleveland, OH, USA.
3. Scientific Institute San Raffaele, Milan, Italy.

Results from a phase II study showed that 40mg dose of glatiramer acetate (GA) was possibly more effective than the currently approved 20mg dose in reducing MRI activity and clinical relapses. To evaluate the safety, tolerability, and efficacy of GA 40mg compared to the 20mg dose.

Patients with definite MS (revised McDonald criteria), with at least one documented relapse in the 12 months prior to screening, or at least two documented relapses in the 24 months prior to screening, and EDSS score 0-5.5, were enrolled. Subjects were evaluated at screening, baseline, and at months 1, 2, 3, 6, 9, and 12. The primary endpoint was the rate of confirmed relapses observed during the study.

A total of 136 centers in 20 countries participated in the trial. Of the 1262 subjects screened, 1155 were randomized to GA 20mg (n=586) or 40mg (n=569). The groups were well-matched at baseline on demographic, clinical, and MRI characteristics. Annualized relapse rate (ARR) in the last year prior to study was 1.498. The primary efficacy endpoint was similar in both groups (relative risk=1.07, p=0.4859) with mean ARR of 0.33 for the 20 mg and 0.35 for the 40 mg group and 0.27 for those who completed one year treatment. Seventy-seven % of the patients remained relapse-free in both groups. Both groups showed a reduction in the mean number of gadolinium-enhancing and new T2 lesions over time with a trend for a faster reduction in the first trimester in the 40mg dose compared with 20mg dose. Both doses were well-tolerated with a safety profile similar to that observed in previous studies of 20mg GA.
In RRMS patients, both GA 40 mg and the currently approved 20mg doses were safe and well-tolerated, and were equally effective in reducing clinical relapses and MRI activity.


Randomized, prospective, rater-blinded, four-year, pilot study to compare the effect of daily versus every-other-day glatiramer acetate 20 mg subcutaneous injections in relapsing-remitting multiple sclerosis
O. Khan1; C. Caon1; I. Zak1; Z. Latif1; R. Penmesta1; F. Bao1; S. Rageb1; A. Hudson1; A. Tselis1
1. Wayne State University School of Medicine, Detroit, MI, USA.
 
The recommended dose of GA in RRMS is 20 mg subcutaneous (SC) daily (QD) although the optimal dose remains unknown. There is considerable interest in alternate dosing regimens of GA in RRMS. Daily SC injectable therapy can be challenging for long-term patient compliance.

We conducted a pilot trial to compare the effect of GA 20 mg SC daily versus every other day (QOD) in RRMS. The primary endpoint was based on a composite of clinical, MRI, and immunologic outcomes.

Treatment naïve RRMS patients were randomized to GA 20 mg SC QD or QOD and followed prospectively for 2 years. After 2 years, patients in each group were given the option to continue or switch to the other group, and followed for an additional 2 years. EDSS was recorded every 6 months by a rater blinded to dosing allocation. Brain MRI scans were obtained at baseline, and years 2 and 4. Blood for immunologic testing was obtained at baseline and multiple time points after randomization.
30 patients were randomized to GA 20 mg SC given QD or QOD. Both groups were well-matched for age, disease duration, EDSS, relapse rate, T2W and gadolinium (Gd) enhancing lesions. After 2 years, there were no differences in the relapse rate, disease progression, Change in T2W lesion volume, or Gd enhancing lesions between the two groups. In vitro proliferation of GA-responsive T-cells and Th1/Th2 cytokine expression did not differ between the two groups at any time point after randomization. After 2 years, all patients in the QD group opted to switch to QOD. After a total of 4 years of prospective follow-up, there was no difference between the QD-QOD cross over group and the always QOD group. Additional data on imaging and immunologic outcomes will be presented.

This pilot study suggests that GA 20 mg SC administered QD or QOD may be equally effective in RRMS. This may have implications for the long-term use of GA. However, large multi-center studies are warranted to confirm our findings and to identify the optimal dose of GA in RRMS.


VLA-4 antisense: an oligonucleotide targeting VLA-4 mRNA (ATL1102) significantly reduces new active lesions in patients with relapsing-remitting multiple sclerosis
V. Limmroth1; F. Barkhof2; N. Desem3
1. Department of Neurology, Cologne City Hospitals, University of Cologne, Cologne, Germany.
2. Department of Radiology, MS Center Amsterdam, VU University Medical Center, Amsterdam, Netherlands.
3. Antisense Therapeutics Ltd, Melbourne, VIC, Australia.
 
Antisense oligonucleotides (ASOs) are an innovative new class of drugs that inhibit the expression of proteins by sequence-specific binding to the protein’s mRNA. ATL1102 is a 2nd generation antisense inhibitor of CD49d, a subunit of Very Late Antigen 4 (VLA-4) which plays a key role in cell adhesion to vessel walls. VLA-4 blockade, as shown by monoclonal antibodies such as natalizumab, prevents activated lymphocytes from migrating into the CNS and significantly reduces disease activity in MS.

To evaluate VLA-4 Antisense (ATL1102) in the treatment of RR-MS
Randomized, double-blind, placebo-controlled multicenter Phase-IIa trial. 77 patients with RR-MS were treated for 8 weeks with either 200mg of ATL1102 or placebo subcutaneously twice weekly and evaluated for 16 weeks. MRI scans were performed at screening, and then monthly over 16 weeks. Primary efficacy variable: cumulative number of new active lesions (CNNAL; new gadolinium-enhancing T1 lesions (T1-Gd), new or enlarging T2 lesions) on MRIs taken at weeks 4, 8 and 12. Secondary efficacy variable: cumulative volume of T1-Gd lesions (CVT1L) on MRIs taken at weeks 4, 8 and 12.

ITT population: 74 patients with a valid baseline MRI and at least one post-baseline MRI scan after first injection of study medication (n=39 placebo, n=35 ATL1102). ATL1102 showed a significant reduction, 54.4%, in CNNAL (6.2 placebo, 3.0 ATL1102; p=0.01). A reduction of 66.7% (p=0.002) was observed in the cumulative number (weeks 4,8,12) of new T1-Gd lesions with ATL1102. A reduction in CVT1L was also observed under ATL1102 but did not reach significance (589.4 mm3 placebo, 358.0 mm3 ATL1102; p=0.1068). Adverse events that were more frequent under ATL1102 included mild to moderate injection site reactions and a tendency for decreased platelet counts which were reversible after treatment interruption.

This proof-of-concept study of a drug designed to inhibit VLA-4 mRNA showed a significant reduction of the cumulative number of new active lesions in RR-MS patients following 8 weeks of treatment. These promising results warrent further investigation.
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BM Stem Cells

Postby Brainteaser » Sun Sep 21, 2008 6:49 pm

I agree with mrhodes - the Karussis study findings I would think are quite amazing. For advanced MS, for 13 MS subjects to go from a mean EDSS of 6.8 to 5.7 over 6 months, with presumably no complementary treatments is fantastic! Am I missing something here because I have raised Karussis' and Scolding's studies with my neuro who dismisses them, saying that there has not even been success with mice. BTW, what have been the results with Scolding's work? - I haven't seen anything yet, although I think his study was IV compared with Karussis being intrathecal.
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Postby dignan » Wed Sep 24, 2008 12:19 pm

Phil, I haven't found anything recent on Scoldings work, but am also interested to see how the UK MSC trial unfolds. I just saw this article (below) today that is distantly related and suggests to me that these studies are on the right track, but we probably have a few more steps to go until we find the right type of stem cell or precursor/progenitor cell:


Cell Type Counts in Spinal Therapy

September 24, 2008 - Technology Review - Small differences in the type of cells used for transplantation therapies can have a big impact on outcome. In experiments published in the current edition of the Journal of Biology, scientists from the University of Rochester and the University of Colorado found that transplanting a certain type of cell improved motor function in rats whose spinal cords had been severed. However, transplantation of a closely related cell type had little benefit and actually made the animals more sensitive to pain.

The findings illustrate the importance of differentiating stem cells before transplanting them into injured tissue, an issue that has been under great debate as stem cell-based therapies approach human testing. "This study demonstrates for the first time the dynamics of developmentally different populations of [cells], which we need to take into account," says Martin Marsala, a professor of anesthesiology who teaches at the University of San Diego and was not involved in the study.

For the rest of the article:
http://www.technologyreview.com/Biotech/21414/
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Postby dignan » Fri Sep 26, 2008 11:45 am

As Bromley mentioned in his Campath post today, the Accelerated Cure folks have their excellent summary of the event up now: http://www.bostoncure.org:8080/node/3403

One thing they added, which confirms what I've been thinking for a little while now is this:

Teriflunomide development plan; moving forward (Aaron Miller)

Dr. Miller outlined the upcoming phase 3 teriflunomide trials. TEMSO
will include 1,088 relapsing MS subjects, will last for 108 weeks,
will evaluate relapse rate, progression, MRI, and safety/tolerability,
and will be placebo-controlled. TOWER will include 1,110 subjects,
will have a variable duration (minimum 48 weeks), will evaluate
clinical endpoints, and will also be placebo-controlled.

Questions and answers

Q: Why was it necessary to have both TOWER and TEMSO?

A: The FDA is reluctant to approve drugs without two phase 3 trials.
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