Department of Neuroinflammation, Institute of Neurology, Queen Square, London, WC1N 3BG, UK. R.Farrell@ion.ucl.ac.uk
Multiple sclerosis (MS) is the most common neurological cause of disability in young people. The disease-modifying treatments, IFN-beta and glatiramer acetate, have been widely available over the last decade and have shown a beneficial effect on relapse rate and magnetic resonance imaging parameters of disease activity; however, their effect on disease progression and disability is modest. Therefore, the search for alternative treatment strategies continues. As understanding of the heterogeneous pathophysiology of MS has increased, emphasis has shifted to more selective therapy that targets components of the inflammatory cascade and the promotion of remyelination and neuroprotection. These agents target the blood-brain barrier, systemic immune dysfunction, local inflammation and neurodegeneration. Combination therapies are being investigated for patients who fail first-line treatments. Many new drugs are being developed and tested that address these issues with the aim of finding a more effective and convenient therapy. These include humanized monoclonal antibodies such as daclizumab (IL-2 antagonist), oral immunomodulators such as sirolimus and statins and neuroprotective agents such as NMDA antagonists and Na+-channel blockers. Many of the treatments discussed in this review are still at early stages of development, but provide exciting potential treatment options; others have proved disappointing in larger extended-phase studies.
Cancer Center, Ordway Research Institute, Albany, NY 12208, USA.
Humans die from age-related diseases, which are deadly manifestations of the aging process. In order to extend life span, an anti-aging drug must delay age-related diseases. All together age-related diseases are the best biomarker of aging. Once a drug is used for treatment of any one chronic disease, its effect against other diseases (atherosclerosis, cancer, prostate enlargement, osteoporosis, insulin resistance, Alzheimer's and Parkinson's diseases, age-related macular degeneration) may be evaluated in the same group of patients. If the group is large, then the anti-aging effect could be validated in a couple of years. Startlingly, retrospective analysis of clinical and preclinical data reveals four potential anti-aging modalities.
Inhibition of HBV gene expression and replication by stably expressed interferon-alpha1 via adeno-associated viral vectors.
Zhi Li, Hong Yao, Yan Ma, Qingming Dong, Yangchao Chen, Ying Peng, Bo-jian Zheng, Jian-dong Huang, Chu-yan Chan, Marie C Lin, Joseph J Sung, Kwok Yun Yuen, Hsiang-fu Kung, Ming-Liang He
Department of Microbiology, The University of Hong Kong, Hong Kong, China.
BACKGROUND Interferon-alpha2 (IFNalpha2) is routinely used for anti-hepatitis B virus (HBV) treatment. However, the therapeutic efficiency is unsatisfactory, particularly in East Asia. Such inefficiency might be a result of the short half-life, relatively low local concentration and strong side-effects of interferons. Frequent and repeated injection is also a big burden for patients. In the present study, a single dose of vector-delivered IFNalpha1 was tested for its anti-HBV effects. METHODS Adeno-associated viral vector (AAV-IFNalpha1) was generated to deliver the IFNalpha1 gene into hepatocytes. IFNalpha1, hepatitis B surface (HBsAg) and e (HBeAg) antigens were measured by enzyme-linked immunosorbent assay and/or western blotting. The level of viral DNA was measured by quantitative real-time polymerase chain reaction. RESULTS AAV-IFNalpha1 effectively transduced HBV-producing cells (HepAD38) and mouse hepatocytes, where IFNalpha1 was expressed in a stable manner. Both intracellular and extracellular HBsAg and HBeAg were significantly reduced in vitro. In the HBV-producing mice, the concentration of IFNalpha1 in the liver was eight-fold higher than that in plasma. Compared with control groups, HBeAg/HBsAg antigen levels were reduced by more than ten-fold from day 1-5, and dropped to an undetectable level on day 9 in the AAV-IFNalpha1 group. Concurrently, the level of viral DNA decreased over 30-fold for several weeks. CONCLUSIONS A single dose administration of AAV-IFNalpha1 viral vector displayed prolonged transgene expression and superior antiviral effects both in vitro and in vivo. Therefore, the use of AAV-IFNalpha1 might be a potential alternative strategy for anti-HBV therapy.
Hotchkiss Brain Institute and the Department of Clinical Neurosciences, University of Calgary, Alberta, Canada. email@example.com
Activated T cells, particularly those of the T-helper (Th) 1 subset, have the capacity to kill neurons. Strategies for preventing such damage may include deviation of activated T cells into the Th2 subset (e.g., via use of glatiramer acetate), alteration of functional properties of Th1 cells (e.g., through use of interferon [INF]-beta or IV immunoglobulin), and inhibition of activated cell migration into the CNS (e.g., by employing INF-beta or natalizumab). Matrix metalloproteinase-9 (MMP-9) also causes neuron death in neurotoxicity models, and examination of medications with MMP inhibitory activity indicates that minocycline is capable of preventing such damage. Minocycline also has other properties relevant to conferring neuroprotection, such as inhibition of microglial activity and apoptosis pathways. In a small pilot study in patients with relapsing-remitting multiple sclerosis, minocycline treatment produced favorable outcomes in terms of gadolinium-enhancing lesions and clinical course. Further studies are needed to establish whether experimental neuroprotection strategies involving these mechanisms may be translated into preventing neurodegeneration in multiple sclerosis.
Cyclophilin D inactivation protects axons in experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis.
Michael Forte, Bruce G Gold, Gail Marracci, Priya Chaudhary, Emy Basso, Dustin Johnsen, Xiaolin Yu, Jonathan Fowlkes, Micha Rahder, Katie Stem, Paolo Bernardi, Dennis Bourdette
Vollum Institute, Oregon Health and Science University, Portland, OR 97239, USA. firstname.lastname@example.org
Multiple sclerosis (MS) is the leading cause of neurological disability in young adults, affecting some two million people worldwide. Traditionally, MS has been considered a chronic, inflammatory disorder of the central white matter in which ensuing demyelination results in physical disability [Frohman EM, Racke MK, Raine CS (2006) N Engl J Med 354:942-955]. More recently, MS has become increasingly viewed as a neurodegenerative disorder in which neuronal loss, axonal injury, and atrophy of the CNS lead to permanent neurological and clinical disability. Although axonal pathology and loss in MS has been recognized for >100 years, very little is known about the underlying molecular mechanisms. Progressive axonal loss in MS may stem from a cascade of ionic imbalances initiated by inflammation, leading to mitochondrial dysfunction and energetic deficits that result in mitochondrial and cellular Ca2+ overload. In a murine disease model, experimental autoimmune encephalomyelitis (EAE) mice lacking cyclophilin D (CyPD), a key regulator of the mitochondrial permeability transition pore (PTP), developed EAE, but unlike WT mice, they partially recovered. Examination of the spinal cords of CyPD-knockout mice revealed a striking preservation of axons, despite a similar extent of inflammation. Furthermore, neurons prepared from CyPD-knockout animals were resistant to reactive oxygen and nitrogen species thought to mediate axonal damage in EAE and MS, and brain mitochondria lacking CyPD sequestered substantially higher levels of Ca2+. Our results directly implicate pathological activation of the mitochondrial PTP in the axonal damage occurring during MS and identify CyPD, as well as the PTP, as a potential target for MS neuroprotective therapies.
Immunotherapeutic Approaches in MS: Update on Pathophysiology and Emerging Agents or Strategies 2006.
Department of Neurology, Bayerische Julius-Maximilians-Universität Würzburg, Josef-Schneider-Str. 11, D-97080 Würzburg, Germany. email@example.com.
Multiple sclerosis (MS) is a chronic disabling disease with significant implications for patients and society. The individual disease course is difficult to predict due to the heterogeneity of clinical presentation as well as radiological and pathological findings. Although its etiology still remains unknown, the last decade has generated considerable success in understanding the underlying pathophysiology of MS. In addition to its view as a prototypic inflammatory autoimmune disorder, recent data support the importance of primary and secondary neurodegenerative mechanisms such as oligodendrocyte death, axonal loss and ion channel dysfunction. The deepened understanding of the immunopathogenesis as well as the limited effectiveness of the currently approved disease modifying therapies have led to a tremendous number of trials investigating potentially new drug targets. Emerging treatments take into account the different immunopathological mechanisms as well as strategies to protect against axonal damage or to promote remyelination. This review provides a compilation of novel immunotherapeutic strategies or new aspects of known immunotherapeutic agents which have evolved recently. The pathogenetic rationale of these novel drug targets for the treatment of MS as well as accompanying preclinical and clinical data are highlighted.
Mediators of apoptosis Fas and FasL predict disability progression in multiple sclerosis over a period of 10 years.
Division of Biomedical Research, TNO Quality of Life, P.O. Box 2215, 2301 CE, Leiden, The Netherlands.
TNF-alpha, IL-12p35, IL-12p40, IL-4, IL-10, TGF-beta1, CCR3, CXCR3, CCR5, Fas and FasL mRNA levels in PBMC of 25 multiple sclerosis (MS) patients were quantified at baseline by real-time PCR according to a post-hoc study design. The baseline values of the different markers were analysed with respect to their correlation with the increase in disability over a period of 10 years. High levels of Fas mRNA were associated with a favourable disease course in relapsing-remitting (RR) MS (R2 = 0.74, P = 0.0001, n = 13), as measured by the Expanded Disability Status Scale (EDSS); high levels of FasL mRNA were associated with relatively mild disease progression (R2 = 0.86, P = 0.0001, n =12) in secondary progressive (SP) MS. These findings suggest that Fas-mediated apoptosis plays a major role in the mechanism underlying long-term disease progression in MS.:
Department of Obstetrics and Gynaecology, San Martino Hospital and University of Genoa, Largo R. Benzi 1, 16132 Genoa, Italy. firstname.lastname@example.org
In women with multiple sclerosis, pregnancy does not have a long-term adverse effect on lifetime disability; however, there is an increased risk of relapses during the postpartum. Therapies taken during pregnancy may have adverse effects on pregnancy outcome. The small number of pregnancies included in most studies, particularly those evaluating the risks related to the administration of immunomodulating drugs, do not allow firm conclusions to be drawn with regards to their safety. Therefore, until more information regarding safety is available, glatiramer acetate, mitoxantrone and interferon-beta should be discontinued before an anticipated pregnancy. By contrast, glucocorticoids can be used to treat acute relapses during pregnancy.
Department of Neurology, Scientific Institute H. San Raffaele, Via Olgettina 48, I-20132 Milan, Italy. email@example.com.
So far, off-label recommendation of a combination therapy is mainly based on phase II study evidence and on largely accepted expert opinions. Combination therapy represents a new, more global strategy, to increase the possible benefits with the combined use of already available disease-modifying therapies or with other new agents, having an acceptable theoretical rationale and a good safety and efficacy profile. The therapeutic strategies of the near future will try to select among different and individualised combinations of drugs, with distinct mechanisms of action, and possibly with synergistic activity, to maximise benefits and minimise risks. The combination approach is at present particularly recommended for more aggressive forms of multiple sclerosis (MS) and for non-responders to available drugs, although the theoretical rationale and accumulated experience would suggest its use in all MS patients right from the beginning of the disease.
Other papers by authors:
Neutralizing Antibodies Are Associated with a Reduction of Interferon-β Efficacy during the Treatment of Japanese Multiple Sclerosis Patients.
Douglas Kazutoshi Sato, Ichiro Nakashima, Toshiyuki Fukazawa, Yuko Shimizu, Yuji Tomizawa, Kazumasa Yokoyama, Tatsuro Misu, Paul I Creeke, Rachel Farrell, Gavin Giovannoni, Yasuto Itoyama, Kazuo Fujihara, Masashi Aoki
Department of Neurology, Tohoku University Graduate School of Medicine.
Multiple sclerosis (MS) is a chronic immune-mediated inflammatory demyelinating disease of the central nervous system. Interferon-β (IFN-β) has been used as the first line therapy for MS treatment in Japan, but patients treated with IFN-β may develop antibodies, known as neutralizing antibodies (NAbs), which abrogate its therapeutic effects. Intramuscular IFN-β 1a and subcutaneous IFN-β 1b are currently available in Japan, but large-scale studies evaluating the prevalence and clinical implications of NAbs against these IFN-β preparations in MS patients have only been performed in Caucasian populations. NAbs positivity has been reported to be associated with HLA-DRB1 alleles, suggesting that the positivity might differ among populations with distinct genetic backgrounds. Clinical information and sera were collected from 229 consecutive MS patients treated with IFN-β in 4 centers in Japan. Sera were tested for NAbs using a luciferase reporter gene assay. In total, 5.2% of IFN-β-1a-treated patients (4/77) and 30.3% of IFN-β-1b-treated patients (46/152) were positive for Nabs. The frequency of NAbs was highest in patients treated for 13 to 24 months. Clinical relapse and contrast-enhancing lesions in the magnetic resonance imaging increased together with NAbs titers in this group. In conclusion, the prevalence of NAbs in Japanese MS patients is similar to that in Caucasian populations and is associated with an increase in disease activity. Therefore, routine NAbs testing is recommended also in Asian populations to ensure the early identification of patients who would benefit from a change in therapy.
Validating parameters of a luciferase reporter gene assay to measure neutralizing antibodies to IFNbeta in multiple sclerosis patients.
Neuro-Immunology Laboratory, University of British Columbia, Vancouver, Canada.
Neutralizing antibodies (NAbs) can occur in some multiple sclerosis (MS) patients receiving interferon beta (IFNbeta) therapy. NAbs reduce drug bioavailabity and high NAb titers reduce drug efficacy. We describe the validation of the R. Farrell and G. Giovannoni luciferase reporter gene assay to measure NAbs to INFbeta. We assayed 163 sera from IFNbeta treated MS patients with an optimized luciferase method and compared the results to those obtained with the reference cytopathic effect (CPE) method using A549 cells and an encephalomyocarditis virus (EMCV). Binding antibodies (BAbs) were measured using a capture ELISA as a screening test for NAbs in the CPE assay. NAb status measured by the luciferase and the ELISA/CPE method did not yield a significant difference. Log10 NAb titers obtained from the luciferase assay and the A549/EMCV CPE methods correlated very well. The inter-assay coefficient of variation for titers was between 17.8-29.3%, and the intra-assay coefficient of variation was between 6.3-15.2%. The luciferase assay is reliable, appropriately sensitive and requires less time than the currently available NAb methods.
Re: Neutralizing antibodies to interferon beta-1b are not associated with disease worsening in multiple sclerosis.
Rachel Farrell, Klaus Bendtzen, Antonio Bertolotto, Berwyn Clark, Manuel Comabella, Florian Deisenhammer, Anna Fogdell-Hahn, Gavin Giovannoni, Hans Peter Hartung, Bernard Hemmer, Jan Hillert, Ludwig Kappos, Joep Killestein, Raija Lindberg, Xavier Montalban, Chris Polman, Per Soelberg Sorensen
J Immunol. 2012 Nov 30;: 23203924
Early Growth Response Gene-2 Controls IL-17 Expression and Th17 Differentiation by Negatively Regulating Batf.
Tizong Miao, Meera Raymond, Punamdip Bhullar, Emma Ghaffari, Alistair L J Symonds, Ute C Meier, Gavin Giovannoni, Suling Li, Ping Wang
Blizard Institute of Cell and Molecular Science, Barts and London School of Medicine and Dentistry, London E1 2AD, United Kingdom.
Early growth response gene (Egr)-2 is important for the maintenance of T cell homeostasis and controls the development of autoimmune disease. However, the underlying mechanisms are unknown. We have now discovered that Egr-2, which is induced by TGF-β and IL-6, negatively regulates the expression of IL-17, but not IL-2 or IFN-γ, in effector T cells. In the absence of Egr-2, CD4 T cells produce high levels of Th17 cytokines, which renders mice susceptible to experimental autoimmune encephalomyelitis induction. T cells lacking Egr-2 show increased propensity for Th17, but not Th1 or Th2, differentiation. Control of IL-17 expression and Th17 differentiation by Egr-2 is due to inhibition of Batf, a transcription factor that regulates IL-17 expression and Th17 differentiation. Egr-2 interacts with Batf in CD4 T cells and suppresses its interaction with DNA sequences derived from the IL-17 promoter, whereas the activation of STAT3 and expression of retinoic acid-related orphan receptor γt are unchanged in Th17 cells in the absence of Egr-2. Thus, Egr-2 plays an important role to intrinsically control Th17 differentiation. We also found that CD4 T cells from multiple sclerosis patients have reduced expression of Egr-2 and increased expression of IL-17 following stimulation with anti-CD3 in vitro. Collectively, our results demonstrate that Egr-2 is an intrinsic regulator that controls Th17 differentiation by inhibiting Batf activation, which may be important for the control of multiple sclerosis development.
J Med Virol. 2013 Jan ;85 (1):128-31 23154877
Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University, London, UK. firstname.lastname@example.org.
High IgG titers against the Epstein-Barr virus nuclear antigen, EBNA-1, have been strongly correlated with the risk of developing multiple sclerosis. ELISAs are used frequently to measure EBNA-1 titers, however concerns remain regarding the accuracy of results. Ordering absolute results into rank quintiles for analysis may be preferable. Using 120 serum samples, two commercially available ELISAs (produced by DiaSorin and VirionSerion) were compared, both in terms of absolute results and rank quintiles. The positive predictive value of the VirionSerion ELISA was 99.1% when compared to the DiaSorin ELISA, however, the negative predictive value was 64.3%. Sensitivity and specificity were acceptable at 95.5% and 90.0%, respectively. There was poor correlation between absolute results, R(2) = 0.49; and the kappa coefficient for rank quintiles was low at 0.23. Although sensitivity and specificity appear adequate, the poor negative predictive value and kappa coefficient are of major concern. Care must be taken when selecting assays for experimental use. J. Med. Virol. 85:128-131, 2012. © 2012 Wiley Periodicals, Inc.
The month of birth effect in multiple sclerosis: systematic review, meta-analysis and effect of latitude.
Queen Mary University of London, Blizard Institute, Barts and the London School of Medicine and Dentistry, London UK.
BACKGROUND: Month of birth has previously been described as a risk factor for multiple sclerosis (MS). This has been hypothesised to be related to maternal vitamin D levels during pregnancy, although conclusive evidence to support this is lacking. To date, no large studies of latitudinal variation in the month of birth effect have been performed to advance this hypothesis. METHODS: Previously published data on month of birth from 151 978 MS patients were compared to expected birth rates. A linear regression model was used to assess the relationship between latitude and observed:expected birth ratio of MS patients for each month. RESULTS: Analysis of all reported data demonstrated a significant excess of MS risk in those born in April (observed:expected 1.05, p=0.05) and reduction in risk in those born in October (0.95, p=0.04) and November (0.92 p=0.01). A conservative analysis of 78 488 patients revealed an excess MS risk in those born in April (1.07, p=0.002) and May (1.11, p=0.0006), and a reduced risk in those born in October (ratio 0.94, p=0.004) and November (0.88, p=0.0002). A significant relationship between latitude and observed:expected ratio was demonstrated in December, and borderline significant relationships in May and August. CONCLUSIONS: Month of birth has a significant effect on subsequent MS risk. This is likely to be due to ultraviolet light exposure and maternal vitamin D levels, as demonstrated by the relationship between risk and latitude.
Lancet. 2012 Oct 31;: 23122652
Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: a randomised controlled phase 3 trial.
Jeffrey A Cohen, Alasdair J Coles, Douglas L Arnold, Christian Confavreux, Edward J Fox, Hans-Peter Hartung, Eva Havrdova, Krzysztof W Selmaj, Howard L Weiner, Elizabeth Fisher, Vesna V Brinar, Gavin Giovannoni, Miroslav Stojanovic, Bella I Ertik, Stephen L Lake, David H Margolin, Michael A Panzara, D Alastair S Compston
Mellen Center, Cleveland Clinic, Cleveland, OH, USA. Electronic address: email@example.com.
BACKGROUND: The anti-CD52 monoclonal antibody alemtuzumab reduced disease activity in a phase 2 trial of previously untreated patients with relapsing-remitting multiple sclerosis. We aimed to assess efficacy and safety of first-line alemtuzumab compared with interferon beta 1a in a phase 3 trial. METHODS: In our 2 year, rater-masked, randomised controlled phase 3 trial, we enrolled adults aged 18-50 years with previously untreated relapsing-remitting multiple sclerosis. Eligible participants were randomly allocated in a 2:1 ratio by an interactive voice response system, stratified by site, to receive intravenous alemtuzumab 12 mg per day or subcutaneous interferon beta 1a 44 μg. Interferon beta 1a was given three-times per week and alemtuzumab was given once per day for 5 days at baseline and once per day for 3 days at 12 months. Coprimary endpoints were relapse rate and time to 6 month sustained accumulation of disability in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT00530348. FINDINGS: 187 (96%) of 195 patients randomly allocated interferon beta 1a and 376 (97%) of 386 patients randomly allocated alemtuzumab were included in the primary analyses. 75 (40%) patients in the interferon beta 1a group relapsed (122 events) compared with 82 (22%) patients in the alemtuzumab group (119 events; rate ratio 0·45 [95% CI 0·32-0·63]; p<0.0001), corresponding to a 54·9% improvement with alemtuzumab. Based on Kaplan-Meier estimates, 59% of patients in the interferon beta 1a group were relapse-free at 2 years compared with 78% of patients in the alemtuzumab group (p<0·0001). 20 (11%) of patients in the interferon beta 1a group had sustained accumulation of disability compared with 30 (8%) in the alemtuzumab group (hazard ratio 0·70 [95% CI 0·40-1·23]; p=0·22). 338 (90%) of patients in the alemtuzumab group had infusion-associated reactions; 12 (3%) of which were regarded as serious. Infections, predominantly of mild or moderate severity, occurred in 253 (67%) patients treated with alemtuzumab versus 85 (45%) patients treated with interferon beta 1a. 62 (16%) patients treated with alemtuzumab had herpes infections (predominantly cutaneous) compared with three (2%) patients treated with interferon beta 1a. By 24 months, 68 (18%) patients in the alemtuzumab group had thyroid-associated adverse events compared with 12 (6%) in the interferon beta 1a group, and three (1%) had immune thrombocytopenia compared with none in the interferon beta 1a group. Two patients in the alemtuzumab group developed thyroid papillary carcinoma. INTERPRETATION: Alemtuzumab's consistent safety profile and benefit in terms of reductions of relapse support its use for patients with previously untreated relapsing-remitting multiple sclerosis; however, benefit in terms of disability endpoints noted in previous trials was not observed here. FUNDING: Genzyme (Sanofi) and Bayer Schering Pharma.
Sci Rep. 2012 ;2 :770 23105968
Estimating the proportion of variation in susceptibility to multiple sclerosis captured by common SNPs.
Department of Biological Sciences, Simon Fraser University , Burnaby, British Columbia, V5A 1S6, Canada.
Multiple sclerosis (MS) is a complex disease with underlying genetic and environmental factors. Although the contribution of alleles within the major histocompatibility complex (MHC) are known to exert strong effects on MS risk, much remains to be learned about the contributions of loci with more modest effects identified by genome-wide association studies (GWASs), as well as loci that remain undiscovered. We use a recently developed method to estimate the proportion of variance in disease liability explained by 475,806 single nucleotide polymorphisms (SNPs) genotyped in 1,854 MS cases and 5,164 controls. We reveal that ~30% of MS genetic liability is explained by SNPs in this dataset, the majority of which is accounted for by common variants. These results suggest that the unaccounted for proportion could be explained by variants that are in imperfect linkage disequilibrium with common GWAS SNPs, highlighting the potential importance of rare variants in the susceptibility to MS.
PLoS One. 2012 ;7 (10):e46730 23094030
Giammario Ragnedda, Giulio Disanto, Gavin Giovannoni, George C Ebers, Stefano Sotgiu, Sreeram V Ramagopalan
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom ; Nuffield Department of Clinical Neurosciences (Clinical Neurology), University of Oxford, The West Wing, John Radcliffe Hospital, Oxford, United Kingdom ; Division of Neurology, Department of Clinical and Experimental Medicine, University of Sassari, Sassari, Italy.
Genetic factors play an important role in determining the risk of multiple sclerosis (MS). The strongest genetic association in MS is located within the major histocompatibility complex class II region (MHC), but more than 50 MS loci of modest effect located outside the MHC have now been identified. However, the relative candidate genes that underlie these associations and their functions are largely unknown. We conducted a protein-protein interaction (PPI) analysis of gene products coded in loci recently reported to be MS associated at the genome-wide significance level and in loci suggestive of MS association. Our aim was to identify which suggestive regions are more likely to be truly associated, which genes are mostly implicated in the PPI network and their expression profile. From three recent independent association studies, SNPs were considered and divided into significant and suggestive depending on the strength of the statistical association. Using the Disease Association Protein-Protein Link Evaluator tool we found that direct interactions among genetic products were significantly higher than expected by chance when considering both significant regions alone (p<0.0002) and significant plus suggestive (p<0.007). The number of genes involved in the network was 43. Of these, 23 were located within suggestive regions and many of them directly interacted with proteins coded within significant regions. These included genes such as SYK, IL-6, CSF2RB, FCLR3, EIF4EBP2 and CHST12. Using the gene portal BioGPS, we tested the expression of these genes in 24 different tissues and found the highest values among immune-related cells as compared to non-immune tissues (p<0.001). A gene ontology analysis confirmed the immune-related functions of these genes. In conclusion, loci currently suggestive of MS association interact with and have similar expression profiles and function as those significantly associated, highlighting the fact that more common variants remain to be found to be associated to MS.
Latest similar papers:
Neurol Res. 2012 Aug 21;: 22910063
OBJECTIVES: To evaluate safety and efficacy of add-on low-dose azathioprine or interferon (IFN)-beta in patients with active multiple sclerosis despite monotherapy. METHODS: This retrospective observational study evaluated 5-year data from 85 patients with active multiple sclerosis despite monotherapy with either IFN-beta or azathioprine, who received add-on azathioprine or IFN-beta, respectively. In a subgroup of 23 patients, 10-year data were analysed. Clinical (relapse frequency, disability) and laboratory effects were compared preceding and following the addition of second drug and between the two treatment regimens. Potential serious adverse events were evaluated. RESULTS: The add-on treatment triggered a drop in annualised relapse rate by approximately 1.5 points sustained over 5 and 10 years. No effect on disability was observed. Simultaneously, white blood cell and lymphocyte counts decreased, being below the physiological levels in 8?26% and 13?52% of patients at each time point, respectively. The drop in relapse rate was independent from the dosage of azathioprine or changes in lymphocyte count. Comparison between the two treatment regimens showed that, with the exception of lymphocyte count, these effects were triggered by the add-on of interferon but not azathioprine. The combination therapy was well tolerated; however, after 5 years on treatment a moderately increased incidence of cancer was observed. CONCLUSIONS: IFN-beta as add-on to azathioprine decreases relapse activity in active multiple sclerosis. In contrast, azathioprine add-on in patients with suboptimal response to IFN-beta does not improve the control over the disease activity.
Staff Neurologist, Department of Neurology, National Pediatric Hospital Dr Juan P. Garrahan, Billinghurst 850. Buenos Aires, 1174 Argentina.
Children and adolescents with multiple sclerosis (MS) are reported to show high rates of relapse early in the course of the disease as well as cognitive deterioration over time. Immunomodulatory therapies developed for adult MS patients are currently the standard first-line agents for most paediatric MS patients. Available data indicate that the three interferon-beta preparations and glatiramer acetate are safe and well tolerated in children and adolescents with MS, and provide preliminary indications of efficacy in terms of relapse rate reduction. However, these treatments are only partly effective and their routes of administration can be bothersome, particularly for children. Emerging therapies for MS offer promise for improved disease control and long-term clinical outcome, with the advantage of an oral administration for some of them. The future approval of these new medications requires clinical trial consideration of such therapies in the paediatric population. Many of these new agents carry a higher risk for serious adverse events with increased toxicity and still undefined long-term side effects. There are ethical issues as well as issues related to feasibility that must be borne in mind when planning investigation trials for new pharmacological agents in the paediatric population, including immunological maturity, key period of exposure to numerous community-acquired infections, neurodevelopmental factors, in addition to short-term and long-term age-related toxicities. Furthermore, the lack of a large enough paediatric MS population worldwide limits some designs and the feasibility of participation in all the studies. Emerging new therapies have the potential to optimize the care of both paediatric and adult patients with MS. Future treatment trials in children and adolescents with MS will require a multicentre design, definition and selection of key outcome measures, and identification of the most promising therapies. Risks versus benefits of each specific treatment should be weighed and comprehensively discussed.
Multiple Sclerosis Clinic of Central Texas, University of Texas Medical Branch, Round Rock, Texas 78681, USA. firstname.lastname@example.org
PURPOSE OF REVIEW The aims of this article are to review emerging therapies for multiple sclerosis (MS) and to consider new approaches to assessment and achievement of treatment success in patients with this disease. RECENT FINDINGS A number of disease-modifying therapies for MS, including oral agents, are in advanced development and likely to be available soon. Fingolimod has been approved recently by the US Food and Drug Administration. Agents in development include alemtuzumab, BG-12, daclizumab, teriflunomide, laquinimod, and B-cell-targeted monoclonal antibodies ocrelizumab and ofatumumab. The advent of emerging efficacious therapies has set the stage for re-evaluation of treatment goals for patients with MS. Freedom from disease, defined by the absence of relapses, disability progression, and radiologic evidence of disease activity, is increasingly seen as the measure of treatment success. SUMMARY New MS treatments may provide the basis for aggressive early intervention in patients with MS and intensification of treatment when disease is not controlled. The availability of therapies that can achieve higher treatment goals may significantly improve long-term outcomes for MS patients.
John Radcliffe Hospital, University of Oxford Medical School, Oxford, UK. email@example.com
PURPOSE OF REVIEW Multiple sclerosis (MS) is a chronic inflammatory neurological condition typically affecting women of childbearing age. This review addresses questions that often arise in this patient group during pregnancy including the effects of pregnancy on relapse rates and long-term disease course, up-to-date advice on the use of disease-modifying MS treatments during pregnancy, the management of relapses in pregnancy and postpartum and current advice on breast feeding. RECENT FINDINGS Pregnancy is associated with a reduction in relapse frequency most marked in the final trimester with a comparable increase in relapse risk in the first 3 months postpartum. Studies examining exposure to MS therapies glatiramer acetate and interferon-beta during pregnancy have produced few negative outcomes offering the possibility of offering treatment until conception. Although initial data suggested breast feeding reduced MS relapses, the latest study demonstrated no significant benefit. SUMMARY Pregnancy is safe in most MS patients and does not negatively influence MS disease course overall. Use of disease-modifying treatments around conception should be considered on a case-by-case basis, weighing risks of drug exposure against risks of relapses. Whether breast feeding produces beneficial effects on MS relapses remain inconclusive.
Department of Neurology, Heinrich Heine University, Moorenstrasse 5, 40255 Düsseldorf, Germany.
Interferon β and glatiramer acetate have been available for the treatment of multiple sclerosis (MS) for over a decade and their efficacy and safety are well established. These agents have detectable effects on the immune system, but have not been associated with a breakdown of immune surveillance. Novel MS therapies have been approved, or are awaiting approval, that differ from established immunotherapies with regard to their mechanisms of action, modes of administration, adverse-effect profiles and, possibly, the clinical and paraclinical benefits that they may provide for patients. Neurologists will soon be required to make complex treatment decisions with their patients on the basis of very limited clinical data and evidence. Under these circumstances, optimal assessment of risks and benefits will be challenging. In this Review, the anticipated benefits of novel therapies, including reduction in disease activity, possible prevention of disability, and improvement in quality of life, are outlined. In addition, the current acceptance of potential risks--including serious or even life-threatening adverse effects, the likelihood of which may rise with increased cumulative exposure to a particular agent--by patients with MS will be reviewed.
Clin Immunol. 2011 Mar 17;: 21420365
Chronic inflammation and neurodegeneration are the main pathological traits of multiple sclerosis that coexist in all stages of the disease course, with complex and still nonclarified relationships. Currently licensed medications have efficacy to control aspects related to inflammation, but have been unable to modify pure progression. Experimental work has provided robust evidence of the immunomodulatory and neuroprotective properties that cannabinoids exert in animal models of multiple sclerosis. Through activation of the CB2 receptor, cannabinoids modulate peripheral blood lymphocytes, interfere with migration across the blood-brain barrier and control microglial/macrophage activation. CB1 receptors present in neural cells have a fundamental role in direct neuroprotection against several insults, mainly excitotoxicity. In multiple sclerosis, several reports have documented the disturbance of the endocannabinoid system. Considering the actions demonstrated experimentally, cannabinoids might be promising agents to target the main aspects of the human disease.
Central Texas Neurology Consultants, 16040 Park Valley Dr, Bldg B, Ste 100, Round Rock, TX 78681, USA. firstname.lastname@example.org
A variety of emerging therapies for the treatment of multiple sclerosis (MS) are currently in development or have recently been approved by the US Food and Drug Administration (FDA). These new agents offer novel mechanisms of action and potentially improved efficacy over existing first-line MS therapies. Much attention has been given to emerging therapies delivered orally which, at minimum, will likely improve long-term adherence over existing agents delivered via injection. This article reviews the mechanisms of action, efficacy, and safety and tolerability of 4 emerging oral therapies for MS: cladribine, laquinimod, fingolimod, and dalfampridine. The first 3 of these agents are in late development and may enter the market within the next year and a half. Cladribine, laquinimod, and fingolimod have demonstrated impressive efficacy in terms of clinical outcomes, such as annualized relapse rate and change in disability scores, as well as magnetic resonance imaging variables. Dalfampridine, which has already been approved by the FDA, is indicated as a symptomatic therapy to improve walking in MS patients. Based on existing data, these agents appear to have tolerable side-effect profiles, although the long-term safety profiles of these drugs have yet to be elucidated. It remains to be seen whether the safety profiles of these disease-modifying drugs will allow them to displace existing first-line therapies or if agents such as dalfampridine will become additional options alongside current dominant therapies.
Back to the future for multiple sclerosis therapy: focus on current and emerging disease-modifying therapeutic strategies.
Department of Immunology, National Institute of Neuroscience, NCNP, Tokyo, Japan.
The last decade has seen numerous advances in the treatment of multiple sclerosis with six immunotherapeutic agents licensed for use. Although these therapeutic agents have powerful effects upon the inflammatory phase of disease, they have limitations in treating the progression of disability and in their safety profile. This review focuses on our current understanding of first- and second-line treatments for multiple sclerosis, including combination therapies, and also discusses the most promising novel therapeutic strategies on the horizon. Such agents include orally administered immunosuppressive drugs, monoclonal antibodies, antigen-specific tolerance, and neural protection and repair strategies. The challenge ahead lies in the delivery of potent drugs to inhibit inflammation and neurodegeneration while limiting side effects. Further elucidation of the pathophysiology of disease may provide new clinical targets and disease-relevant biomarkers that, in combination with proteomics, may help personalize treatment to individual patients.
Neurol Res. 2010 Nov ;32 (9):981-5 20223094
Effects of adjunct glucosamine sulfate on relapsing-remitting multiple sclerosis progression: preliminary findings of a randomized, placebo-controlled trial.
Department of Neurology, Medical School, Isfahan University of Medical Sciences, Iran.
OBJECTIVES Glucosamine has been safely used to relieve osteoarthritis. The aim of this preliminary study was to evaluate the effect of glucosamine sulfate in combination with current disease modifying therapy on the prevention of progression of relapsing-remitting multiple sclerosis (RRMS). METHODS A phase II double-blind placebo-controlled randomized clinical trial conducted between February and October 2007 included 97 patients with confirmed RRMS aged 17-55 years. They were randomly allocated to receive 6 months of treatment with either oral glucosamine sulfate (1000 mg/day) or placebo combined with disease-modifying therapy. Response to treatment was assessed at 6 months. Primary and secondary outcome measures were number of relapse and changes in mean Expanded Disability Status Scale (EDSS). RESULTS In 46 patients treated with glucosamine sulfate, mean (SD) relapse rate decreased from 1.1 (0.7) at baseline to 0.4 (0.5) at the end of study period (P<0.05). In the 51 patients treated with placebo, the mean (SD) relapse rate did not change. After 6 months, 63.0% of patients receiving glucosamine sulfate remained relapse-free compared to 54.9% of those given placebo (P>0.05). Average EDSS at the end of trial did not differ between groups (mean difference:-0.1; 95% CI:-0.5-0.2). DISCUSSION Adding glucosamine sulfate to routine disease modifying-therapy had no significant effect on relapse rate or disease progression during the treatment period. A larger phase-III multicenter study of glucosamine sulfate in RRMS is warranted to more assess the efficacy of this intervention.
Continuous long-term immunomodulatory therapy in relapsing multiple sclerosis: results from the 15-year analysis of the US prospective open-label study of glatiramer acetate.
C Ford, A D Goodman, K Johnson, N Kachuck, J W Lindsey, R Lisak, C Luzzio, L Myers, H Panitch, J Preiningerova, A Pruitt, J Rose, H Rus, J Wolinsky
Department of Neurology and the Clinical and Magnetic Resonance Research Center and Multiple Sclerosis Specialty Clinic, University of New Mexico Health Sciences Center, University of New Mexico School of Medicine, Pete and Nancy Domenici Hall, 1101 Yale Boulevard NE, Albuquerque, NM 87131, USA. email@example.com
The ongoing US Glatiramer Acetate (GA) Trial is the longest evaluation of continuous immunomodulatory therapy in relapsing-remitting multiple sclerosis (RRMS). The objective of this study was to evaluate up to 15 years of GA as a sole disease-modifying therapy. Two hundred and thirty-two patients received at least one GA dose since study initiation in 1991 (mITT cohort), and 100 (43%, Ongoing cohort) continued as of February 2008. Patients were evaluated every 6 months using the Expanded Disability Status Scale (EDSS). Mean GA exposures were 8.6 +/- 5.2, 4.81 +/- 3.69, and 13.6 +/- 1.3 years and mean disease durations were 17, 13, and 22 years for mITT, Withdrawn and Ongoing cohorts, respectively. For Ongoing patients, annual relapse rates (ARRs) maintained a decline from 1.12 +/- 0.82 at baseline to 0.25 +/- 0.34 per year; 57% had stable/improved EDSS scores (change < or = 0.5 points); 65% had not transitioned to secondary progressive multiple sclerosis (SPMS); 38%, 18%, and 3% reached EDSS 4, 6, and 8. For all patients on GA therapy (the mITT cohort), ARRs declined from 1.18 +/- 0.82 to 0.43 +/- 0.58 per year; 54% had stable/improved EDSS scores; 75% had not transitioned to SPMS; 39%, 23%, and 5% reached EDSS 4, 6, and 8. In conclusion, multiple sclerosis patients with mean disease duration of 22 years administering GA for up to 15 years had reduced relapse rates, and decreased disability progression and transition to SPMS. There were no long-term safety issues.