Bioavailable central nervous system disease-modifying therapies for multiple sclerosis

Abstract

Disease-modifying therapies for relapsing multiple sclerosis reduce relapse rates by suppressing peripheral immune cells but have limited efficacy in progressive forms of the disease where cells in the central nervous system play a critical role. To our knowledge, alemtuzumab, fumarates (dimethyl, diroximel, and monomethyl), glatiramer acetates, interferons, mitoxantrone, natalizumab, ocrelizumab, ofatumumab, and teriflunomide are either limited to the periphery or insufficiently studied to confirm direct central nervous system effects in participants with multiple sclerosis. In contrast, cladribine and sphingosine 1-phosphate receptor modulators (fingolimod, ozanimod, ponesimod, and siponimod) are central nervous system-penetrant and could have beneficial direct central nervous system properties.

Keywords: central nervous system; cladribine; fingolimod hydrochloride; multiple sclerosis; ozanimod; ponesimod; siponimod; sphingosine 1 phosphate receptor modulators.

Figure 1

Typical clinical course of MS. The clinical course of MS is heterogenous, but RRMS is the most common subtype characterized by an initial episode of neurological symptoms (CIS) followed by periods of remissions and relapses. Some patients have an initial diagnosis of primary progressive MS, which is associated with progressive decline. Over time, improvement during remissions wane, and disability accumulates, with most patients developing secondary progressive MS. In secondary progressive MS, neurodegeneration is accompanied with a decline in brain volume. CIS, clinically isolated syndrome; MS, multiple sclerosis; RRMS, relapsing-remitting multiple sclerosis. Source: Adapted (colors revised, text edited/moved, and content removed) from Håkansson et al. (2). under Creative Commons Attribution NonCommercial 4.0 International License (https://creativecommons.org/licenses/by-nc/4.0/).

Figure 2

Pathophysiology of multiple sclerosis. (A) In the early stages of MS, relapses coincide CNS inflammation and demyelination that are typically discernible as white matter lesions via MRI. Peripheral immune cell infiltration can occur from meningeal blood vessels (across the BBB), the subarachnoid space, or the choroid plexus (across the blood-CSF barrier). These infiltrates may then accumulate in perivascular spaces and enter the CNS parenchyma, and along with activated CNS-resident microglia and astrocytes, promote demyelination and oligodendrocyte and neuroaxonal injury through direct contact-dependent mechanisms or via soluble inflammatory and neurotoxic mediators. (B) In the later stages of MS, progressive neurological decline is accompanied by CNS atrophy. Immune cell infiltration is dampened, but CNS inflammation persists. Meningeal tertiary lymphoid-like structures can also contribute to late-stage inflammation in SPMS. Irrespective of MS subtype, CNS-resident innate immune cells may contribute to chronic inflammation. Astrocytes produce ligands and factors that can promote microglial recruitment and activation while also preventing remyelination at the sites of neuroaxonal injury by inhibiting progenitor cell development into mature oligodendrocytes. APC, antigen-presenting cell; BBB, blood-brain barrier; CCL, chemokine ligand; CNS, central nervous system; CSF, cerebrospinal fluid; FDC, follicular dendritic cell; GM, grey matter; IFN-y, interferon gamma; IL, interleukin; MAIT, mucosal-associated invariant T cell; MRI, magnetic resonance imaging; MS, multiple sclerosis; NO, nitric oxide; RNS, reactive nitrogen species; ROS, reactive oxygen species; SPMS, secondary progressive multiple sclerosis; TH, T helper. Adapted from Dendrou et al. (38).