In a previous study carried out by the Biomedical Research Institute (BIOMED), a new protein was discovered (SPAG16 isoform 2) which is attacked by antibodies naturally produced by the body in a group of MS patients. This protein is a possible autoantigen in the pathological process of MS. There is virtually nothing known about the function of this protein or the possible role it may play in the development and progress of MS. Therefore this project will attempt to gain a better insight into the biological properties of SPAG16 isoform 2, and examine the relevance of this new potential autoantigen in the MS pathological process.

Autoimmune diseases results from a harmful reaction of the immune system against certain cells or cell components of the patient. In multiple sclerosis, misguided T lymphocytes recognize components of the central nervous system and mount a chronic inflammatory reaction against it.  To promote an immune reaction properly, T lymphocytes are dependent on certain signals coming from specialized antigen-presenting cells: the dendritic cells. This is also the case in autoimmune reactions. Dendritic cells deliver various so-called "costimulatory" signals. These latter signals can be manipulated using blocking reagents, to prevent T cell activation and potentially also harmful autoimmune reactions. At the same time it can be possible to retain the activity of a regulatory subset of T lymphocytes (Treg cells), which down-regulate auto-reactivity, as these Treg cells are less dependent on costimulation. This could result in long term effects, even after withdrawal of blocking reagents. Therefore, it will be tried in this project to manipulate costimulation in order to prevent effector T cell activation, while still allowing Treg activation, and thus to permanently suppress the autoimmune process.

The aim of our project, entitled "Immunological bio-markers of acute inflammation in MS", is to detect the changes in expression of certain cytokines that play a key role in the disease's attack and remission mechanisms. These molecules can be either over-expressed or under-expressed in the different phases of MS, and the highlighting of such changes would make it possible to establish an index of activity of the disease by means of a simple blood test. Such an index could be used to assess the patient's evolution, the need to start a course of treatment, and the degree of effectiveness of said treatment. The target cytokines are the interleukins 4, 9 and 17, which characterise various lymphocytic sub-populations. These lymphocytes' response to the presence of fragments of proteins from the myelin will also be analysed.

Experimental models of multiple sclerosis involve either mouse immunization with myelin peptides or infection with neurotropic viruses, but do not completely reproduce the human disease. The purpose of our project is to examine the consequences of a viral infection on the pathogenic responses triggered by a concomitant immunization and to determine whether this combined stimulation provides a closer model to the disease.

Most are Phase 2 studies, in which the most promising molecules are selected. The most advanced of these concerns fingolimod, the Phase 3 results of which have been published recently and are discussed in Issue 25 of our newsletter.
The Phase 2 studies of three other molecules are encouraging (fumaric acid, cladribine, laquinimod) and will be followed by Phase 3 studies.

Fumaric acid, which is used to treat psoriasis, is an immunomodulator, the mechanisms of which remain elusive, but that possibly stimulates the body's natural defences, in particular by increasing anti-oxidant production. The Phase 2 study was performed on 257 patients divided into four groups: placebo, 120 mg x 2, 120 mg x 3 and 240 mg x 3 per day. As it is increasingly frequent, the placebo group was given the substance after six months, which makes assessment of the effects on progression impossible over such a short period. The best results were achieved by the highest doses, i.e. a 69% decrease in active plaques detected by magnetic resonance (MRI) and a 32% decrease in flare-ups. These results are comparable to those achieved with IFNs. The secondary effects are flashing and gastro-intestinal disturbances. Of greater concern is the fact that 25% of the patients given the high doses left the study due to intolerance.

Cladribine is an immunosuppressant which has long been in use for the treatment of certain blood cancers. Several Phase 2 studies have already been performed for MS. For methodological reasons, the clinical results were difficult to interpret. However, a study of the radiological data showed a definite decrease in active plaques detected by magnetic resonance (MRI). Despite this, the company had abandoned MS potential indications.
Two years ago, a Phase 3 trial on 1327 patients was initiated. The patients were divided into three groups: placebo, 2 immunosuppressive treatments per year (1 tablet a day for 10 days) during 2 consecutive months, and 4 treatments during 4 consecutive months per year. The duration of the study was 2 years. Later, all patients were treated with 2 treatments a year of cladribine. The first results were released in the press, showing a decrease of exacerbations by 58% (higher than with IFNs) at the low dose and 55% at the high dose. Cladribine is an extremely powerful immunosuppressant and its effects can last for over a year. It may be surmised that its effect on active plaques detected by MRI will be considerable. The study included a placebo group for 2 years, which makes it possible to assess the effect of the drug on the progression of the disability, and it is likely that cladribine will slow down this progression. The long-term secondary effects are opportunistic infections and disturbances of the hematopoietic system. This molecule has been fast-tracked by the FD.

Laquinimod is an immunomodulator, the mechanisms of which are at present little-known, but which mainly has an anti-inflammatory effect. Two Phase 2 studies on the mother molecule (linomide/roquinimex) had shown a decrease in active plaques detected by magnetic resonance (MRI) but had had to be stopped due to severe complications. A clinical test on 306 patients has been published recently, which comprised 3 groups: placebo, 0.3 mg/day and 0.6 mg/day. Although the 0.3 mg/day dose had no significant effect on active plaques detected by magnetic resonance (MRI), the 0.6 mg dose caused them to decrease by 55%. The reduction in the number of exacerbations was 33%, i.e. comparable to that achieved with IFN βs. The duration of the test was too short to assess the effect on the progression of the disability. Secondary effects included pains in the joints and chest, flu-like states, viral infections and liver enzyme disturbances. Laquinimod has also been fast-tracked by the FDA.

There are approximately 80 studies concerning 30 molecules which could be administered by mouth. Except fingolimod, some have been used for years in the treatment of immune or cancerous diseases. Although their tolerance is generally well-known, they are usually employed for short periods only. As MS is a chronic disease, the treatment also needs to be "chronic". Long-term tolerance therefore remains a major problem for the assessment of the risk/benefit ratio of such new treatments. With 20 years' hindsight, it is known that long-term tolerance of IFN βs and copraxone is highly acceptable. Although their effectiveness is limited, that of most new molecules (with the exception of the immunosuppressants, which are far less well tolerated) is hardly better.

Oral treatments will very likely be available within the next few years. However, for the same efficacy, the comfort of oral administration should not justify an increase in the risk of adverse reactions. As these often occur only after several years, it is a matter for legitimate concern that the FDA has fast-tracked some of these molecules.

Dr Richard E. Gonsette
President

Winners of the Charcot Fund 2009 :

The spearhead of the research carried out at the REVAL Onderzoeksinstituut Hasselt (established in 2005) is the effects of supervised exercise therapy on muscle power, function, quality of movement and quality of life among people with multiple sclerosis.
Attention has recently become focused on arm and hand function, an area where little scientific research has been carried out so far, even though this largely determines people's autonomy in daily life. Interactive robots have recently become available that can be used to make intensive arm movements in a virtual environment. This technology is highly promising but nothing is as yet known about either the relationship between performance in a virtual environment and arm function or the effects of robotics training compared with more conventional power training.
The researchers would like to thank the Charcot Research Fund for the support provided to purchase the measuring apparatus needed to objectively record the possibilities for movement of the arm in general and the hand in particular. Such measurements would be helpful as the conventional functional tests currently used in the clinic lack precision when mapping out the possibilities for movement and the quality of the movement.

The role played by lipids in initiating and/or resorbing neuro-inflammatory conditions is now acknowledged. Our hypothesis is that the lipids may play an important role in the physiopathology of multiple sclerosis, and that the type of lipids present in the central nervous system varies depending on the stage and/or the phase of the pathology. We are therefore proposing to identify the lipids whose levels are affected during the development of experimental auto-immune encephalitis in mice in order to then endeavour to determine the role they may play in the development of this pathology.

Multiple sclerosis (MS) is a disease that leads to increasing handicap as a result of the inflammation of the spinal cord and brain. The cause is still largely unknown. In our research project, we are focusing on the dysfunction of the astrocytes (the 'support cells' in the brain). In MS patients these astrocytes lack certain receptors (beta2-adrenergic receptors) that are crucial to the proper working of the brain. The aim of our study is to gain a better insight into the role of this receptor deficiency so as to further unravel the pathology of MS and develop new treatments.

Multiple sclerosis (MS) is the most common chronic inflammatory disease of the central nervous system (CNS).
Compound A (CpdA), a molecule derived from a Namibian desert plant, has recently been characterized as a novel compound with strong anti-inflammatory capacities, displaying limited side effects compared to conventional glucocorticoids, which still remain the most effective drugs for the treatment of MS. Based on initial observations, we propose this selective glucocorticoid receptor modulator CpdA as a lead compound with promising anti-inflammatory characteristics useful to treat EAE, the main animal model for MS. The aim of our research  is a further characterization of this compound in EAE and a subsequent study with more stable derivatives to ultimately be able to develop novel therapeutics for the treatment of multiple sclerosis.