Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system that involves demyelination and axonal degeneration. Although substantial progress has been made in drug development for relapsing–remitting MS, treatment of the progressive forms of the disease, which are characterized clinically by the accumulation of disability in the absence of relapses, remains unsatisfactory. This unmet clinical need is related to the complexity of the pathophysiological mechanisms involved in MS progression. Chronic inflammation, which occurs behind a closed blood–brain barrier with activation of microglia and continued involvement of T cells and B cells, is a hallmark pathophysiological feature. Inflammation can enhance mitochondrial damage in neurons, which, consequently, develop an energy deficit, further reducing axonal health. The growth-inhibitory and inflammatory environment of lesions also impairs remyelination, a repair process that might protect axons from degeneration. Moreover, neurodegeneration is accelerated by the altered expression of ion channels on denuded axons. In this Review, we discuss the current understanding of these disease mechanisms and highlight emerging therapeutic strategies based on these insights, including those targeting the neuroinflammatory and degenerative aspects as well as remyelination-promoting approaches.
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The authors acknowledge the many trainees and collaborators who have contributed to our knowledge on multiple sclerosis. S.F. is grateful for grant support from the Medical Faculty of Ruhr-University Bochum (FoRUM). V.W.Y is grateful for operating grant support from the Canadian Institutes of Health Research, the Multiple Sclerosis Society of Canada and the Alberta Innovates – Health Solutions CRIO Team program.
S.F. and V.W.Y. have filed provisional patent applications at the US Food and Drug Administration (US patent application no. 62/412,555, entitled ‘Combination Therapy with Minocycline and Hydroxychloroquine for the Treatment of Multiple Sclerosis (MS)’ and US patent application no. 62/412,534, entitled ‘Treatment for Progressive Multiple Sclerosis’). S.F. has received travel support from Biogen Idec and Genzyme, speaker’s honoraria from Novartis, board honoraria from Celgene and grant support from Novartis, unrelated to this article. J.R.P. declares no competing interests. R.G. has received speaker’s and board honoraria from Baxter, Bayer Schering, Biogen Idec, CLB Behring, Genzyme, Merck Serono, Novartis, Stendhal, Talecris and Teva. His department has received grant support from Bayer Schering, BiogenIdec, Genzyme, Merck Serono, Novartis and Teva. All of R.G.’s declarations are unrelated to the content of this article. V.W.Y. has received speaker’s and advisory board honoraria from Biogen, EMD Serono, Roche, Novartis, Sanofi-Genzyme and Teva, and educational grants from Biogen, EMD Serono, Roche, Novartis, Sanofi-Genzyme and Teva.
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- Neuromyelitis optica spectrum disorder
Inflammatory disorder of the central nervous system mediated by disease-specific antibodies against aquaporin-4, leading to severe immune-mediated demyelination and axonal damage.
- Normal-appearing white matter
(NAWM). An area in the white matter without obvious lesions or significant abnormalities, such as axonal damage, astrogliosis and microgliosis.
- Normal-appearing grey matter
(NAGM). An area in the grey matter without obvious lesions.
- Experimental autoimmune encephalitis
(EAE). An inflammatory animal model of multiple sclerosis, mediated by inoculation of myelin components with adjuvants.
- Gadolinium-enhancing lesions
T1 lesions showing contrast agent (gadolinium) enhancement on magnetic resonance imaging.
- T2 lesions
Hyperintense magnetic resonance imaging sequences, indicating multiple sclerosis lesion load.
- Clinically isolated syndrome
(CIS). The first clinical episode of neurological symptoms lasting at least 24 h, with features that are indicative of multiple sclerosis.
An increase in the number of astrocytes due to damage.
- Periplaque white matter
The area around lesions in the white matter.
- Iron chelation
Binding of iron by a chelating agent.
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Faissner, S., Plemel, J.R., Gold, R. et al. Progressive multiple sclerosis: from pathophysiology to therapeutic strategies. Nat Rev Drug Discov 18, 905–922 (2019). https://doi.org/10.1038/s41573-019-0035-2
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