Therapeutic Approaches To Multiple Sclerosis

Multiple Sclerosis (MS) is one of the most common inflammatory diseases that affects the central nervous system. It is moderated by both environmental and genetic factors, and the most common pathological features are demyelinated lesions in the central nervous system. The disease progresses over time from having reversible relapse episodes (CIS: clinically isolated symptoms, RRMS: relapsing–remitting MS) to permanent neurological changes and clinical disability (SPMS: secondary progressive MS). As opposed to experiencing episodes, some patients gradually progress from the onset of the disease (PPMS: primary progressive MS). New therapeutic approaches are trying to target different aspects of MS to ameliorate the quality of patient’s life. The management of MS currently includes disease modifying treatments (DMT) and therapeutics to address the symptoms3. Based on the classification of the current state of disease, two different approaches of DMT are considered.

During escalation therapy, the immune system is modulated using 1st line drugs (e.g. IFNβ, glatiramer acetate), which are characterised by their high safety references and low cost. As their effectiveness is moderate, they are usually followed by treatment with a different 1st line or 2nd line (e.g. Alemtuzumab) drugs. Upon non-optimal responses, a 3rd line (e.g. Mitoxantrone) drug treatment is used. An alternative disease handling approach is the transplantation of autologous haematopoietic stem cells, which is chosen for a small number of cases.

Induction therapy is used on patients with more aggressive MS, this strategy supresses and recalibrates the immune system. Malfunctioning immune cells get deleted, and this rapidly decreases the inflammation during MS. This is usually followed by less invasive treatments such as 1st line drugs. In addition, multiple cycles of induction therapy are possible, but the next line of treatment should be reconsidered after each repetition of cycles. Over time, the disease progression might change, therefore careful consideration of treatment methods and conscientious monitoring of patients are necessary.

1st line drugs have excellent safety records and have been used for treatment of MS since the 1990s’. Although side effects are not serious (mostly injection site reactions and flu like symptoms), the effectiveness of these drugs are moderate. The first line of defence acts through signalling pathways resulting in immunomodulatory effects. IFNβ blocks the activation of T cells, intervenes with cytokine production and inhibits the crossing of leukocytes through the blood brain barrier. The mode of action is not entirely clear for other drugs, for example, Glatiramer acetate. It promotes the production of regulatory T cells possibly via making strong connections to MHC-II and drives other immune cells into anti-inflammatory states. It is the only approved safe drug during pregnancy. Other drugs were previously developed to treat different diseases but found to be effective against MS by interfering with lymphocyte development. They inhibit the rapid proliferation of T or B cells by blocking DNA precursor protein formation (Teriflunomide) or inhibiting T-cell antigen presentation via activating NRF2 pathways (Dimethyl fumarate).

2nd and 3rd line drugs possess a more invasive method of treatment and can be both suppressors and modulators of the immune system. Modulatory treatment targets the abnormal movement of lymphocytes. Fingolimod is targeting the S1P pathway, that enables lymphocytes to leave secondary lymphoid organs. Receptor binding of the molecule and later internalisation of the complex blocks the exit of naïve lymphocytes. Similarly, treatment with Natalizumab block integrin binding of leukocytes that hinder T-cell crossing through the blood-brain barrier. Supressing the immune system is a more dramatic intervention. Reducing the number of immune cells can be achieved by targeting surface molecules highly expresses on different immune cells. The use of a humanised antibody leads to the effective deletion of CD52+ (by Alemtuzumab) or CD20+ (by Ocrelizumab) cells, resulting in the reset of the immune system. Other strategies involve interference with DNA processes that leads to specific cell death (Cladribine, Mitoxantrone). The complete repopulation of immune cells can take more than two years, which leaves the patients in a highly susceptible state for autoimmunity and invading agents.

Drugs currently under development aim to reduce disadvantages and increase effectiveness while using the same strategy. Sphingosine (S1P inhibitor) and Ofatumumab (anti-CD20 antibody) are currently under clinical trials. Antigen specific treatment could train the immune system to obtain tolerance against myelin peptides. This reduces the autoreactive responses of T-cells after encountering myelin, therefore they won’t recognise is as a threat. Another promising approach is the promotion of remyelination and protection of neurons. Antagonist antibody Opicinumab was used to block LINGO-1’s inhibition signal that would negatively effect axonal regeneration and myelination. This clinical trial showed the possibility of remyelination and neuronal protection as a new line of treatment replacing immunomodulation.

Although the currently existing treatment options enable promising clinical outcome, they still involve devastating side effects. Studying the mechanisms of different drug treatments leads to a broader understanding of the disease; a vital process, as many of MS’ causes are still unknown.

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