Nature's latest review: In-depth pathology, to explore the only drug that meets the six criteria for MS progression treatment?

Multiple sclerosis (MS) is an inflammatory and degenerative disease of the central nervous system, which has attracted much attention in recent years as a neuroimmune disease
.

From a clinical point of view, the initial course of most patients is mainly relapsing-remitting type (RRMS), which can develop into secondary progressive type (SPMS) over time, and a very small number of patients are initially primary progressive type (PPMS).
Therefore, the latter two are included in progressive MS from an academic point of view
.

In recent years, disease-modifying therapy (DMT) for RRMS has progressed substantially, but compared with that, treatment options for progressive MS remain limited
.

Therefore, exploring how to delay/prevent disease progression has become a hotspot in current MS research
.

The key to whether drugs can work depends on the matching degree of drug treatment mechanism and neuropathology
.

Recently, a review published in the sub-journal of Nature1 comprehensively revealed the neuropathology of progressive MS and developed criteria for evaluating treatment effects in progressive MS
.

Next, let's take a look at how this review evaluates current and future DMT drugs in terms of neuropathological mechanisms of progressive MS
.

Quantitative differences in neuropathology between 01 progressive MS and RRMS largely affect treatment strategies.
The main pathological features of progressive MS include extensive neuronal damage and loss, including neuronal cell bodies, axons, and synapses
.

Also included are marked atrophy of white and grey matter, diffuse demyelination, persistently active lymphocytes (mainly B cells and plasma cells) aggregated in the meninges, or T cells diffusely distributed throughout the central nervous system (CNS), microglia Persistent overexpression and activation of plasmocytes/macrophages, and astrogliosis
.

The review argues that the view that inflammation resolves in progressive MS should be corrected, since progressive MS clearly has both an inflammatory and a neurodegenerative component
.

So, what are the specific mechanisms involved in the neurodegeneration of progressive MS? The mechanisms involved in progressive MS neurodegeneration mainly involve the following points (Figure 1): 01 Neuroinflammation a.
Peripheral inflammation: Peripheral neuroinflammation is present in progressive MS, but due to a relatively repaired blood-brain barrier, leukocyte access to the brain is limited, and focal demyelinating lesions are less common than in RRMS
.

b.
Central inflammation (lymphocyte-mediated): B cells predominate in the pia mater
.

Although B cells are mainly confined to the perivascular spaces of the meninges and retrocapillary veins, they are still thought to cause cortical damage through antibody deposition
.

In addition, B cells release soluble cytotoxic factors that can directly destroy oligodendrocytes and neurons
.

c.
Central inflammation (mediated by myeloid cells): Microglia are activated early in MS and aggregate into "nodules" in normal-appearing brain tissue that may subsequently evolve into active demyelinating lesions
.

Microglia/macrophages can directly exert neurotoxicity through the release of proteases such as myeloperoxidase and apoptosis regulators such as tumor necrosis factor receptor superfamily member 25 (TNFRSF25)
.

Myeloid cells also experience oxidative stress through elevated nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity or reduced levels of redox protective agents
.

Activation of infiltrating mononuclear macrophages, T cells, meningeal or blood-brain barrier (BBB)-associated B lymphocytes, and CNS-intrinsic microglia and astrocytes in the peripheral blood of patients with progressive MS remains It is an important inflammatory cell in progressive MS
.

Because this inflammatory response occurs within the compartmentalized CNS, immunomodulatory agents must be able to enter the CNS to counter deleterious neuroinflammation
.

02 Oxidative stress and mitochondrial dysfunction Oxidative stress refers to the predominance of oxidants in antioxidant defense mechanisms.
Oxygen and nitrogen free radicals can oxidize lipids on the cell surface or in subcellular membranes, leading to their instability and damage
.

The role of oxidative stress in MS lesions has been reported in several studies, and microarray data from brain specimens have shown that oxidative stress in the progressive stages of MS is significantly higher than in lesions associated with other chronic inflammatory diseases or Alzheimer's disease.
more obvious 2
.

Within the parenchyma, CNS-resident microglia are a source of damaging factors
.

Microglia/macrophage secretion of reactive oxygen species (ROS) and reactive nitrogen species (RNS) can cause focal neural axonal degeneration
.

Mitochondria are very sensitive to ROS-mediated oxidative damage, and mitochondrial activity appears to be perturbed in MS patients, and while an initial increase in mitochondrial numbers in axons protects damaged areas, inflammation produces abnormal mitochondria and can be damaged due to kinesin dysfunction.
and hinder the export of mitochondria from the soma to the axon
.

In a mouse model of MS, promoting mitochondrial supply from neuronal soma to axons reduces neural axonal degeneration
.

In addition, potential consequences of mitochondrial damage include failure to complete oxidative phosphorylation, leading to energy exhaustion, which further amplifies oxidative damage and leads to axonal damage
.

03Iron homeostasis Iron is a key cofactor in many CNS processes, and as a transition metal, iron switches between ferrous and ferric forms, giving it a strong capacity to generate oxidative stress
.

Under steady-state conditions, iron is safely managed through a series of mechanisms
.

But inflammation alters iron homeostasis in cells, which exacerbates iron accumulation
.

Iron accumulation, a hallmark feature of MS, has been found to accumulate gradually as the disease progresses3, and iron accumulation is consistent with neurodegeneration4
.

In addition, elevated deep gray matter iron levels are associated with accumulation of disability in MS 5
.

The source of iron accumulation in the brains of MS patients is not known, but it may be due to oligodendrocytes and myelin degeneration that release it extracellularly and are phagocytosed by microglia and macrophages, and the degeneration of these myelin cells produces additional iron accumulation and oxidative stress
.

Iron homeostasis appears to be a major source of oxidative stress in the brain of MS patients, along with NADPH oxidase activation and mitochondrial damage in microglia/macrophages
.

Since excessive oxidative stress can lead to neurodegeneration, alleviating this stress in the CNS is an important therapeutic goal in progressive MS
.

04Insufficient remyelination Promoting remyelination may restore neurological function lost in MS, however patients often have accumulated substantial neurodegeneration at the time of diagnosis, hindering remyelination and functional recovery
.

Therefore, a more feasible outcome of remyelination is to protect the underlying axon from further deterioration
.

Challenges to successful remyelination are currently considered to include oligodendrocyte availability, persistent neuroinflammation that hinders repair, and the diseased microenvironment
.

In addition, remyelination capacity has also been linked to disease progression, with studies finding that remyelination is generally more intense in the early stages of the disease, but declines over time 6
.

Insufficient remyelination in many MS patients leaves exposed axons prone to degeneration, leading to progressive disability, and drug-promoted remyelination is an achievable outcome
.

However, these drugs need to be started before neurodegeneration can outpace functional repair
.

05Other mediators of damage in progressive MS Several studies have identified other mediators of damage in progressive MS, including glutamate excitotoxicity, which triggers N-methyl-D-aspartate (NMDA) receptor dependence influx of calcium ions into neurons 7
.

Furthermore, in cerebellar slice cultures, glutamate exposure directly caused paranodal elongation, resulting in axonal damage 8
.

Accumulation of toxic proteins, such as bassoon9, has also been suggested as a damage mediator
.

Figure 1 Damage mechanism of progressive MS02 Based on the above neuropathological mechanisms, drug standards for evaluating the effective treatment of progressive MS were formulated Based on the above discussion, the review concluded that in order to reduce the disease burden of progressive MS, therapeutic drugs should meet the following criteria (Figure 2): (1) the drug must be able to enter the CNS; (2) the drug should neutralize the cytotoxicity of T cells and B cells within the CNS; (3) the drug should antagonize the harmful effects of microglia/macrophages properties; (4) the drug should eliminate oxidative stress and mitochondrial damage; (5) the drug should promote remyelination to locally protect axons; (6) the drug should have the ability to directly protect axons and neurons
.

Figure 2 Success criteria for drug treatment of progressive MS In order to explore whether the DMT drugs currently approved for the treatment of RRMS meet the above criteria for the treatment of progressive MS, the author has organized the main studies and reviews of these DMT drugs, and summarized them in Table 1 below.
Representation: Table 1 Whether the current DMT meets the criteria for affecting progressive MS According to the table summarized in the review, it can be seen that among the above approved DMT drugs, only siponimod meets all 6 criteria proposed in the review
.

Sinimod is a sphingosine-1-phosphate (S1P) receptor modulator that selectively binds to receptor 1 (S1PR1) and receptor 5 (S1PR5) with high affinity
.

In adoptive metastatic autoimmune encephalomyelitis (EAE), siponimod reduces meningeal inflammation and potential cortical demyelination 10
.

In addition, it was found to attenuate microgliosis and astrogliosis in EAE, reducing oxidative stress and mitochondrial damage 10,11
.

In a transgenic Xenopus tadpole model of MS, sinimod was found to be an effective inducer of remyelination by acting on S1PR5 12
.

Therefore, the review concludes that siponimod meets the above-mentioned criteria for successful pharmacological treatment of progressive MS
.

This notion is supported by siponimod's significant reduction in disability progression in SPMS patients in its phase III EXPAND study
.

In addition, in this trial, individuals treated with siponimod demonstrated a significant benefit in cognitive impairment compared to those in the placebo group, as demonstrated by the symbol digit modalities test (SDMT)
.

According to the review, based on clinical trial data, combined with the six treatment criteria mentioned above, DMTs currently approved for RRMS are ineffective in slowing disability progression in progressive MS, with the exception of siponimod for SPMS
.

While other drugs did not meet all 6 effective treatment criteria, there may be the following reasons: (1) Inadequate access to the CNS, inability to affect some key drivers of disease progression, or initiation of treatment too late in the course of the disease
.

② Even if the drugs acting on the periphery can enter the CNS, the T cells and B cells in the CNS may be less sensitive to the drugs
.

However, real-world data suggest that some drugs, especially high-potency drugs, can slow disability progression or delay progression from RRMS to SPMS 14,15,16
.

In addition to the potential activity of these drugs within the CNS, it may be secondary to suppression of systemic inflammation that protects the CNS from peripheral immune-mediated damage and provides an opportunity for spontaneous neural recovery
.

But neuropathology shows that regardless of the subtype of MS, neurodegeneration occurs early in the disease and leads to future disability progression
.

Therefore, to be beneficial in progressive MS, treatment must be initiated early in the course of the disease and exhibit neuroprotective properties to prevent the accumulation of neurodegeneration
.

03 To explore whether emerging treatments for progressive MS meet the standard of care for progressive MS In addition, there are some emerging treatments for progressive MS (Table 2), including alpha-lipoic acid, BTK inhibitors, ibudilast and statins, As well as some repurposed generic oral medications, such as hydroxychloroquine, metformin, and niacin, which appear to partially meet the aforementioned criteria for the treatment of progressive MS
.

Since progressive MS has significant neuropathological accumulation, multiple drug treatments may be required for different pathogenesis
.

In the future, more clinical studies are needed to evaluate the therapeutic potential of emerging drugs
.

Table 2 Whether a new drug meets the criteria for affecting progressive MS 04Summary MS neurodegenerative changes occur earlier and lead to future disability progression.
Therefore, if a treatment is to be beneficial for progressive MS, treatment needs to be initiated as soon as possible to prevent Against substantial neurodegeneration already present at the time of diagnosis
.

In addition, in terms of treatment strategies, selecting drugs with mechanisms to meet more needs can ensure effective treatment.
Sinimod is the only drug in the currently approved DMT that meets the six criteria for successful treatment of progressive MS proposed in the review.
This may explain why in clinical studies of patients with progressive and relapsing forms of MS, only sinimod has obtained corresponding positive results
.

This article has a deeper understanding of the development of the disease from the pathological mechanism, and also suggests that clinicians need to pay close attention to the changes and progress of the disease, and choose the optimal drug to give to the patient
.

References: 1.
Yong HYF, et al.
Mechanism-based criteria to improve therapeutic outcomes in progressive multiple sclerosis.
Nature Reviews.
Neurology.
2021 Nov 3.
2.
Fischer, MT et al.
Disease-specific molecular events in cortical multiplesclerosis lesions.
Brain 136 , 1799–1815 (2013).
3.
Elkady, AM, Cobzas, D.
, Sun, H.
, Blevins, G.
&Wilman, AH Progressiveiron across accumulation multiple sclerosis phenotypes revealed by sparseclassification of deep gray matter.
J.
Magn.
Reson .
Imaging 46, 1464–1473(2017).
4.
Raz, E.
et al.
Relationship between iron accumulation and white matter injury in multiple sclerosis: a casecontrol study.
J.
Neurol.
262, 402–409 (2015).
5.
Zivadinov, R.
et al.
Brain iron at quantitative MRI is associated with disability in multiple sclerosis.
Radiology 289, 487–496 (2018).
6.
Goldschmidt, T.
, Antel, J.
, Konig, FB, Bruck, W.
&Kuhlmann, T.
Remyelination capacity of the MS brain decreases with disease chronicity.
Neurology 72, 1914–1921 (2009).
7.
Macrez, R.
, Stys, PK, Vivien, D.
, Lipton, SA &Docagne, F.
Mechanisms of glutamate toxicity in multiple sclerosis: biomarker and therapeutic opportunities.
Lancet Neurol.
15, 1089–1102 (2016).
8.
Gallego- Delgado, P.
et al.
Neuroinflammation in the normal- appearing whitematter (NAWM) of the multiple sclerosis brain causes abnormalities at the nodesof Ranvier.
PLoS Biol.
18, e3001008 (2020).
9.
Schattling, B.
et al.
Bassoon proteinopathy drives neurodegeneration in multiple sclerosis.
Nat.
Neurosci.
22, 887–896 (2019).
10.
Ward, LA et al .
Siponimod therapy implicates Th17 cells in a preclinical model of subpial cortical injury.
JCI Insight 5, e132522 (2020).
11.
Gentile, A.
et al.
Siponimod (BAF312) prevents synaptic neurodegeneration inexperimental multiple sclerosis.
J.
Neuroinflammation 13, 207 (2016).
12.
Mannioui, A.
et al.
The Xenopus tadpole: an in vivo model to screen drugsfavoring remyelination.
Mult.
Scler.
24, 1421 –1432 (2018).
13.
Kappos, L.
et al.
Siponimod versus placebo in secondary progressive multiplesclerosis (EXPAND): a double- blind, randomised, phase 3 study.
Lancet 391,1263–1273 (2018).
14.
He , A.
et al.
Timing of high-efficacy therapy for multiple sclerosis: aretrospective observational cohort study.
Lancet Neurol.
19, 307–316 (2020).
15.
Kalincik, T.
et al.
Treatment effectiveness of alemtuzumab compared with natalizumab, fingolimod , and interferon beta in relapsing- remitting multiplesclerosis: a cohort study.
Lancet Neurol.
16, 271–281(2017).
16.
Brown, JWL et al.
Association ofinitial diseasemodifying therapy with later conversion to secondary progressivemultiple sclerosis.
JAMA 321, 175–187(2019).