Multiple sclerosis drug repurposing for neuroregeneration

Peter Göttle,Michael Dietrich,Patrick Küry

Multiple sclerosis (MS) is an autoimmune disorder of the central nervous system (CNS) and is primarily characterized by immune cell infiltration leading to relapses followed by remission phases and a disease course turning progressive over time with neurodegenerative processes taking over (Amin and Hersh,2023).Of note,beyond relapse-associated worsening early in disease progression independent of relapse activity may arise independently of relapse activity and can occur in all phenotypes.Autoimmune-mediated damage of myelin sheaths and the subsequent loss of mature oligodendrocytes are resulting in impaired axonal integrity,neurodegeneration and accounts for irreversible neuronal damage(Kuhlmann et al.,2023).The current landscape of available disease-modifying therapies comprises mainly immunomodulatory drugs that effectively diminish relapses and slow down progression at the onset form of the disease,namely relapsing MS (RMS).In this regard,a number of drugs have been approved as disease-modifying therapies for MS by US Food and Drug Administration and European Medicines Agencies (Box 1).

Box 1 ｜Current disease-modifying therapies including their mode of action

Due to their immunomodulatory mode of action,most of the here listed treatments are very operative within RMS,however,less effective once the disease develops into progressive stages,mainly because autoimmune cells vanish,and neurodegenerative processes take over.Hence,they are not thought to provide neuroprotection or to support re-establishing lost oligodendrocytes and myelin sheaths.At least such unique selling points,exerting neuroprotective and proregenerative effects,remain to be demonstrated.Effective therapies restoring lost functions or able to halt disease worsening by fostering myelin repair activities,therefore still represent a clinical unmet need.This is even more important considering that the already limited endogenous repair capacity of the adult CNS increasingly fails at this stage additionally contributing to irreversible deficits.

Neuroregeneration in MS mainly refers to myelin repair and the replacement of lost oligodendrocytes.Such restoration of existing lesions can occur via recruitment of either parenchymal oligodendroglial precursor cells,or of oligodendrocytes generated from neural stem cells and,to a lesser extent,by pre-existing oligodendrocytes (Moyon et al.,2023),the overall efficiency,however,remains limited.This lack of opportunities inspired science to set the treatment aim to identify pharmacologically active compounds able to promote remyelination.Over the past years,a number of small molecule drugs boosting the intrinsic remyelination capacity in the CNS have been identified based on phenotypical andin silicoscreening approaches,as recently summarized (Manousi and Küry,2021).None of these drugs are in clinical use,but promising candidates are on the way and might indeed be developed and approved for novel treatments.As such strategies are time-consuming and expensive drug repurposing offers an alternative approach by minimizing risks and costs due to the identification of novel/additional targets for known clinically approved drugs.Of the currently applied MS drugs(Box 1),a few substances have already been tested for pro-oligodendroglial and/or neuroprotective activities.

Miron et al.(2010) demonstrated the effects of the non-selective sphingosine 1-phosphate(S1P) receptor modulator fingolimod on myelinrelated processes.Within their studies,fingolimod was shown to modulate multiple neuroglial cell responses,resulting in enhanced remyelination in organotypic slice cultures that maintain the complex cellular interactions of the mammalian brain (Miron et al.,2010).In this respect,fingolimod treatment subsequent to lysolecithininduced demyelination enhanced remyelination and process extension by oligodendroglial precursor cells and mature oligodendrocytes,while increasing microglia numbers and immunoreactivity for the astrocytic marker glial fibrillary acidic protein (Miron et al.,2010).

Furthermore,the selective sphingosine-1-phosphate receptor-1/5 modulator siponimod was shown to exhibit a regenerative and remyelinating potential using multiple animal models such as upon cuprizone-dependent demyelination,in a conditional demyelination model usingXenopus laevis,as well as in experimental autoimmune encephalomyelitis (EAE).Increased remyelination was observed in the cuprizone and tadpole models,with beneficial effects following a bell-shaped dose-response curve.In the EAE model,siponimod attenuated the clinical score and reduced retinal degeneration after both,prophylactic and therapeutic treatment,also in a bell-shaped manner.Inflammatory infiltrates and demyelination of the optic nerve were reduced,which also shifted microglial polarization towards restorative phenotypes (Dietrich et al.,2022).A siponimod-dependent modulation of microglial phenotypes could then also be confirmedex vivoin response to lipopolysaccharide exposure(Gruchot et al.,2022).

Yetano the rapproved first-lineoral immunomodulatory disease-modifying therapies for RMS is teriflunomide.Its primary mode of action relies on the inhibition of pyrimidine biosynthesis in activated lymphocytes thereby inducing a selective and reversible blockade of the mitochondrial enzyme dihydroorotate dehydrogenase.This results in a reduction of activated peripheral T and B lymphocytes.But this substance has also a remarkable regenerative potential given that its application in a cuprizonemediated demyelination model substantially improved axonal remyelinationin vivo(Göttle et al.,2023).Moreover,the oral application also restored mitochondrial integrities in oligodendroglial cells within the affected corpus callosum (Göttle et al.,2023) which nicely complements previous findings on zymosterol accumulation in oligodendrocytes and fostered myelin repair inXenopus laevisupon metronidazole treatment and in lysolecithin demyelinated mice (Martin et al.,2021).Of note,the accumulation of 8,9-unsaturated sterols such as lanosterol and zymosterol has previously been shown to be functionally involved in myelin repair(Hubler et al.,2018).

Apart from attenuation of clinical deficits in EAE mice via immune cell depletion in a compartment-specific manner,the synthetic purine analog cladribine was also shown to exert a neuroprotective effect as it partially restored cortical neuronal network function (Schroeter et al.,2022).

Dimethyl fumarate was approved for the treatment of RMS in 2013 and exerts neuroprotective effects in EAE mice via the NF-E2-related factor 2 antioxidant pathway (Linker et al.,2011).Dimethyl fumarate also reduced retinal degeneration in a primary degenerative mouse model.In these mice,glutathione levels in the retina were increased and histological investigations revealed less microglial activation (Dietrich et al.,2020).Nevertheless,effects on remyelination have not been studied thus far.

Besides these above-mentioned substances,4-aminopyridine is used as symptomatic therapy in several neurological disorders.Its prolongedrelease formulation (fampridine) has been approved for the symptomatic treatment of walking disability in MS.The beneficial effects are explained by the blockade of axonal voltage-gated potassium channels,thereby enhancing signal transduction along demyelinated axons.However,in the EAE model,significant protection from retinal neurodegeneration under 4-aminopyridine treatment was observed.Histology andinvitroexperiments indicated 4-aminopyridinemediated stabilization of myelin and protection of oligodendrocyte precursor cells under oxidative stress conditions (Dietrich et al.,2020).

In summary,out of the 23 currently used drugs for the treatment of RMS,six different substances were currently shown to act in an either neuroprotective or restorative way and manner,interestingly all of which being administrated orally.Nevertheless,it is still a long way along the road in establishing novel regenerative treatments as translational obstacles remain to overcome.Given that preclinical studies assessing functional myelin regeneration are still rather difficult to translate into clinical studies,as the determination of successful outcomes in patients remains to be improved.Moreover,species-specific differences in the molecular profiles of CNS myelin and oligodendrocytes should be considered as well as drug safety and negative pleiotropic effects on otherwise physiologically required homeostatic pathways.Moreover,the window of opportunity to treat MS patients needs to be defined.Whereas within preclinical animal models,this aspect is well-defined,the diversity of lesions as well as the yet unknown remyelination kinetics in MS patients impedes a successful implementation.

The authors’ studies on Siponimod have been financially supported by Novartis (to PK).No conflicts of interest exist between Novartis and Publication of this manuscript.

Peter Göttle,Michael Dietrich,Patrick Küry*

Department of Neurology,Medical Faculty,Heinrich-Heine University,Düsseldorf,Germany

*Correspondence to:Patrick Küry,PhD,kuery@uni-duesseldorf.de.

https://orcid.org/0000-0002-2654-1126(Patrick Küry)

Date of submission:April 24,2023

Date of decision:June 7,2023

Date of acceptance:June 20,2023

Date of web publication:July 20,2023

https://doi.org/10.4103/1673-5374.380901

How to cite this article:Göttle P,Dietrich M,Küry P (2024) Multiple sclerosis drug repurposing for neuroregeneration.Neural Regen Res 19(3):507-508.

Open access statement:This is an open access journal,and articles are distributed under the terms of the Creative Commons AttributionNonCommercial-ShareAlike 4.0 License,which allows others to remix,tweak,and build upon the work non-commercially,as long as appropriate credit is given and the new creations are licensed under the identical terms.

Open peer reviewer:Elena Barbuti,Sapienza University of Rome,Italy.

Additional file:Open peer review report 1.