Emerging small-molecule treatments for multiple sclerosis: focus on B cells

Aaron Gregson, Kaitlyn Thompson, Stella E Tsirka, David L Selwood, Aaron Gregson, Kaitlyn Thompson, Stella E Tsirka, David L Selwood

Abstract

Multiple sclerosis (MS) is a major cause of disability in young adults. Following an unknown trigger (or triggers), the immune system attacks the myelin sheath surrounding axons, leading to progressive nerve cell death. Antibodies and small-molecule drugs directed against B cells have demonstrated good efficacy in slowing progression of the disease. This review focusses on small-molecule drugs that can affect B-cell biology and may have utility in disease management. The risk genes for MS are examined from the drug target perspective. Existing small-molecule therapies for MS with B-cell actions together with new drugs in development are described. The potential for experimental molecules with B-cell effects is also considered. Small molecules can have diverse actions on B cells and be cytotoxic, anti-inflammatory and anti-viral. The current B cell-directed therapies often kill B-cell subsets, which can be effective but lead to side effects and toxicity. A deeper understanding of B-cell biology and the effect on MS disease should lead to new drugs with better selectivity, efficacy, and an improved safety profile. Small-molecule drugs, once the patent term has expired, provide a uniquely sustainable form of healthcare.

Keywords: B cells; MS; Multiple sclerosis; small molecule drugs; sustainable healthcare.

Conflict of interest statement

No competing interests were disclosed.No competing interests were disclosed.No competing interests were disclosed.

Figures

Figure 1.. Causes and progression of multiple…
Figure 1.. Causes and progression of multiple sclerosis (MS).
Several studies now indicate that Epstein–Barr virus infection is necessary (but not causal) for MS to develop. Genetic factors may explain 50% of MS susceptibility whereas environmental factors together with unknowns may combine to trigger immune activation and the subsequent destruction of myelin and oligodendrocytes. This eventually leads to axonal damage and nerve cell death resulting in disability. HERV, human endogenous retrovirus.
Figure 2.. Mechanism of action of cladribine.
Figure 2.. Mechanism of action of cladribine.
Cladribine is taken up into cells by nucleoside transporters and then is phosphorylated to the mono-phosphate (the rate-limiting step) by deoxycytidine kinase, highly expressed in lymphocytes. Subsequent phosphorylation steps produce the active species, the triphosphate. The triphosphate cannot be efficiently degraded by adenosine deaminase, and 5′-nucleotidase has low expression in lymphocytes. This leads to high levels of the cladribine triphosphate, which is toxic to cells by a number of mechanisms, including incorporation into DNA leading to single-stranded breaks.

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