Treatment Of Progressive Multiple Sclerosis Research Articles

UNLOCKING HOPE: OVERCOMING THERAPEUTIC CHALLENGES IN PROGRESSIVE MULTIPLE SCLEROSIS

Progressive forms of multiple sclerosis (MS) present significant therapeutic challenges, underscoring the pressing need for effective treatments in this domain. While relapsing-remitting MS (RRMS) transitions to secondary progressive MS (SPMS) for many patients, others experience primary progressive MS (PPMS) from the diseases onset. Despite similarities in pathophysiology and clinical progression between SPMS and PPMS, treatment options remain limited. The recent approval of ocrelizumab for PPMS marks a notable advancement, though its efficacy is modest. This retrospective study, conducted at the Neurology Department of Mohammed VI University Hospital, evaluates the tolerance and therapeutic efficacy of various treatments in progressive MS. Nineteen patient records spanning six years were analyzed, with therapeutic interventions including Fingolimod, Rituximab, cyclophosphamide-solumedrol, and ocrelizumab. Assessments utilizing the Expanded Disability Status Scale (EDSS) revealed stabilization or improvement in 15.7% of secondary progressive MS and 21% of primary progressive MS patients after 12 months of treatment. The duration of the progressive phase emerged as a key predictor of therapeutic response. Despite the approval of ocrelizumab in Morocco for PPMS, its utilization remains limited, suggesting the need for targeted studies focusing on early-stage clinical progression. Overall, this study underscores the unmet need for effective treatments in progressive MS and highlights ongoing research efforts aimed at addressing this challenge.

Neurodegeneration and demyelination in multiple sclerosis.

Progressive multiple sclerosis (PMS) is an immune-initiated neurodegenerative condition that lacks effective therapies. Although peripheral immune infiltration is a hallmark of relapsing-remitting MS (RRMS), PMS is associated with chronic, tissue-restricted inflammation and disease-associated reactive glial states. The effector functions of disease-associated microglia, astrocytes, and oligodendrocyte lineage cells are beginning to be defined, and recent studies have made significant progress in uncovering their pathologic implications. In this review, we discuss the immune-glia interactions that underlie demyelination, failed remyelination, and neurodegeneration with a focus on PMS. We highlight the common and divergent immune mechanisms by which glial cells acquire disease-associated phenotypes. Finally, we discuss recent advances that have revealed promising novel therapeutic targets for the treatment of PMS and other neurodegenerative diseases.

Progressive multiple sclerosis treatment considerations in the UK: Experience from trials and real-world population

Progressive multiple sclerosis treatment considerations in the UK: Experience from trials and real-world population

PD-L1 positive astrocytes attenuate inflammatory functions of PD-1 positive microglia in models of autoimmune neuroinflammation

Multiple Sclerosis (MS) is a chronic autoimmune inflammatory disorder of the central nervous system (CNS). Current therapies mainly target inflammatory processes during acute stages, but effective treatments for progressive MS are limited. In this context, astrocytes have gained increasing attention as they have the capacity to drive, but also suppress tissue-degeneration. Here we show that astrocytes upregulate the immunomodulatory checkpoint molecule PD-L1 during acute autoimmune CNS inflammation in response to aryl hydrocarbon receptor and interferon signaling. Using CRISPR-Cas9 genetic perturbation in combination with small-molecule and antibody-mediated inhibition of PD-L1 and PD-1 both in vivo and in vitro, we demonstrate that astrocytic PD-L1 and its interaction with microglial PD-1 is required for the attenuation of autoimmune CNS inflammation in acute and progressive stages in a mouse model of MS. Our findings suggest the glial PD-L1/PD-1 axis as a potential therapeutic target for both acute and progressive MS stages.

Deeply 3D-T1-TFE hypointense voxels are characteristic of phase-rim lesions in multiple sclerosis.

The development of new drugs for the treatment of progressive multiple sclerosis (MS) highlights the need for new prognostic biomarkers. Phase-rim lesions (PRLs) have been proposed as markers of progressive disease but are difficult to identify and quantify. Previous studies have identified T1-hypointensity in PRLs. The aim of this study was to compare the intensity profiles of PRLs and non-PRL white-matter lesions (nPR-WMLs) on three-dimensional T1-weighted turbo field echo (3DT1TFE) MRI. We then evaluated the performance of a derived metric as a surrogate for PRLs as potential markers for risk of disease progression. This study enrolled a cohort of relapsing-remitting (n = 10) and secondary progressive MS (n = 10) patients for whom 3T MRI was available. PRLs and nPR-WMLs were segmented, and voxel-wise normalized T1-intensity histograms were analyzed. The lesions were divided equally into training and test datasets, and the fifth-percentile (p5)-normalized T1-intensity of each lesion was compared between groups and used for classification prediction. Voxel-wise histogram analysis showed a unimodal histogram for nPR-WMLs and a bimodal histogram for PRLs with a large peak in the hypointense limit. Lesion-wise analysis included 1075 nPR-WMLs and 39 PRLs. The p5 intensity of PRLs was significantly lower than that of nPR-WMLs. The T1 intensity-based PRL classifier had a sensitivity of 0.526 and specificity of 0.959. Profound hypointensity on 3DT1TFE MRI is characteristic of PRLs and rare in other white-matter lesions. Given the widespread availability of T1-weighted imaging, this feature might serve as a surrogate biomarker for smoldering inflammation. Quantitative analysis of 3DT1TFE may detect deeply hypointense voxels in multiple sclerosis lesions, which are highly specific to PRLs. This could serve as a specific indicator of smoldering inflammation in MS, aiding in early detection of disease progression. • Phase-rim lesions (PRLs) in multiple sclerosis present a characteristic T1-hypointensity on 3DT1TFE MRI. • Intensity-normalized 3DT1TFE can be used to systematically identify and quantify these deeply hypointense foci. • Deep T1-hypointensity may act as an easily detectable, surrogate marker for PRLs.

A neural stem-cell treatment for progressive multiple sclerosis.

A neural stem-cell treatment for progressive multiple sclerosis.

Motor Behavioral Deficits in the Cuprizone Model: Validity of the Rotarod Test Paradigm.

Multiple Sclerosis (MS) is a neuroinflammatory disorder, which is histopathologically characterized by multifocal inflammatory demyelinating lesions affecting both the central nervous system’s white and grey matter. Especially during the progressive phases of the disease, immunomodulatory treatment strategies lose their effectiveness. To develop novel progressive MS treatment options, pre-clinical animal models are indispensable. Among the various different models, the cuprizone de- and remyelination model is frequently used. While most studies determine tissue damage and repair at the histological and ultrastructural level, functional readouts are less commonly applied. Among the various overt functional deficits, gait and coordination abnormalities are commonly observed in MS patients. Motor behavior is mediated by a complex neural network that originates in the cortex and terminates in the skeletal muscles. Several methods exist to determine gait abnormalities in small rodents, including the rotarod testing paradigm. In this review article, we provide an overview of the validity and characteristics of the rotarod test in cuprizone-intoxicated mice.

Novel Drugs in a Pipeline for Progressive Multiple Sclerosis.

Multiple sclerosis (MS) is a widely known inflammatory, demyelinating disease of the central nervous system. The pathogenesis of progressive multiple sclerosis (PMS) is a complex, multi-level process that causes therapeutic difficulties. Along with variables such as age and duration of the disease, pathogenetic mechanisms change from inflammatory to neurodegenerative processes. Therefore, the efficacy of available anti-inflammatory drugs approved for the treatment of PMS, such as ocrelizumab or siponimod, is limited in time. In search of innovative solutions, several research studies have been conducted to evaluate the effectiveness of drugs with neuroprotective or remyelinating effects in PMS, including biotin, ibudilast, simvastatin, alpha-lipoic acid, clemastine, amiloride, fluoxetine, riluzole, masitinib, opicinumab, and lamotrigine. The current review includes those compounds, which have entered the clinical phase of assessment, and the authors discuss future prospects for successful PMS treatment.

Is the effect of drugs in progressive MS only due to an effect on inflammation? A subgroup meta-analysis of randomised trials

Background: It is unclear whether drugs approved for the treatment of progressive multiple sclerosis (PMS) are effective in disability progression only because of their effect on the inflammatory component of the disease. Objective: This meta-analysis aimed to evaluate whether the benefits of PMS treatments are mediated by its effect on the active component of the disease. Methods: We conducted a systematic search to identify randomised, double-blind, placebo-controlled trials evaluating the efficacy of disease-modifying therapies on disability progression for primary or secondary PMS. The primary endpoint of the analysis was disability progression based on the expanded disability status scale. A subgroup meta-analysis evaluated the effects of treatment according to disease activity at baseline. Results: Twelve trials (a total of 8659 PMS cases) were selected. Analysis of the included trials demonstrated that treatment benefit appears to be mainly confined to the group with active disease (hazard ratio (HR) = 0.67; 95% confidence interval (CI): 0.58–0.79) as compared to the group with inactive disease (HR = 0.90; 95% CI: 0.79–1.02, interaction test: p = 0.005). Conclusions: This study showed that the benefit of treating patients with PMS was mostly confined to those with the more active disease. Drugs targeting specific pathological processes leading to disability progression remain necessary.

Disability Progression in SPMS Despite Therapeutic Intervention: Refractory SPMS

New disease-modifying drugs (DMDs), such as ocrelizumab and Siponimod, have been proven to be efficacious for treating progressive multiple sclerosis (MS) and have marked a new era in the treatment of this disease. However, these drugs work on the inflammatory component of the disease, and their potential effect on the neurodegenerative aspect of MS is likely to be modest. Therefore, the treatment of progressive MS continues to be challenging in routine clinical practice. This review summarizes the efficacy of currently approved DMDs for secondary progressive MS and discusses the management of treatment-refractory secondary progressive MS.

Designing Multi-arm Multistage Adaptive Trials for Neuroprotection in Progressive Multiple Sclerosis.

There are few treatments shown to slow disability progression in progressive multiple sclerosis (PMS). One challenge has been efficiently testing the pipeline of candidate therapies from preclinical studies in clinical trials. Multi-arm multistage (MAMS) platform trials may accelerate evaluation of new therapies compared to traditional sequential clinical trials. We describe a MAMS design in PMS focusing on selection of interim and final outcome measures, sample size, and statistical considerations. The UK MS Society Expert Consortium for Progression in MS Clinical Trials reviewed recent phase II and III PMS trials to inform interim and final outcome selection and design measures. Simulations were performed to evaluate trial operating characteristics under different treatment effect, recruitment rate, and sample size assumptions. People with MS formed a patient and public involvement group and contributed to the trial design, ensuring it would meet the needs of the MS community. The proposed design evaluates 3 experimental arms compared to a common standard of care arm in 2 stages. Stage 1 (interim) outcome will be whole brain atrophy on MRI at 18 months, assessed for 123 participants per arm. Treatments with sufficient evidence for slowing brain atrophy will continue to the second stage. The stage 2 (final) outcome will be time to 6-month confirmed disability progression, based on a composite clinical score comprising the Expanded Disability Status Scale, Timed 25-Foot Walk test, and 9-Hole Peg Test. To detect a hazard ratio of 0.75 for this primary final outcome with 90% power, 600 participants per arm are required. Assuming one treatment progresses to stage 2, the trial will recruit ≈1,900 participants and last ≈6 years. This is approximately two-thirds the size and half the time of separate 2-arm phase II and III trials. The proposed MAMS trial design will substantially reduce duration and sample size compared to traditional clinical trials, accelerating discovery of effective treatments for PMS. The design was well-received by people with multiple sclerosis. The practical and statistical principles of MAMS trial design may be applicable to other neurodegenerative conditions to facilitate efficient testing of new therapies.

Astrocyte-Derived Pleiotrophin Mitigates Late-Stage Autoimmune CNS Inflammation.

Astrocytes are the most abundant glial cells in the central nervous system (CNS) with the capacity to sense and react to injury and inflammatory events. While it has been widely documented that astrocytes can exert tissue-degenerative functions, less is known about their protective and disease-limiting roles. Here, we report the upregulation of pleiotrophin (PTN) by mouse and human astrocytes in multiple sclerosis (MS) and its preclinical model experimental autoimmune encephalomyelitis (EAE). Using CRISPR-Cas9-based genetic perturbation systems, we demonstrate in vivo that astrocyte-derived PTN is critical for the recovery phase of EAE and limits chronic CNS inflammation. PTN reduces pro-inflammatory signaling in astrocytes and microglia and promotes neuronal survival following inflammatory challenge. Finally, we show that intranasal administration of PTN during the late phase of EAE successfully reduces disease severity, making it a potential therapeutic candidate for the treatment of progressive MS, for which existing therapies are limited.

Optical Coherence Tomography and Visual Evoked Potentials as Prognostic and Monitoring Tools in Progressive Multiple Sclerosis.

Understanding the mechanisms underlying progression and developing new treatments for progressive multiple sclerosis (PMS) are among the major challenges in the field of central nervous system (CNS) demyelinating diseases. Over the last 10 years, also because of some technological advances, the visual pathways have emerged as a useful platform to study the processes of demyelination/remyelination and their relationship with axonal degeneration/protection. The wider availability and technological advances in optical coherence tomography (OCT) have allowed to add information on structural neuroretinal changes, in addition to functional information provided by visual evoked potentials (VEPs). The present review will address the role of the visual pathway as a platform to assess functional and structural damage in MS, focusing in particular on the role of VEPs and OCT, alone or in combination, in the prognosis and monitoring of PMS.

Stem Cell Therapies for Progressive Multiple Sclerosis.

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system characterized by demyelination and axonal degeneration. MS patients typically present with a relapsing-remitting (RR) disease course, manifesting as sporadic attacks of neurological symptoms including ataxia, fatigue, and sensory impairment. While there are several effective disease-modifying therapies able to address the inflammatory relapses associated with RRMS, most patients will inevitably advance to a progressive disease course marked by a gradual and irreversible accrual of disabilities. Therapeutic intervention in progressive MS (PMS) suffers from a lack of well-characterized biological targets and, hence, a dearth of successful drugs. The few medications approved for the treatment of PMS are typically limited in their efficacy to active forms of the disease, have little impact on slowing degeneration, and fail to promote repair. In looking to address these unmet needs, the multifactorial therapeutic benefits of stem cell therapies are particularly compelling. Ostensibly providing neurotrophic support, immunomodulation and cell replacement, stem cell transplantation holds substantial promise in combatting the complex pathology of chronic neuroinflammation. Herein, we explore the current state of preclinical and clinical evidence supporting the use of stem cells in treating PMS and we discuss prospective hurdles impeding their translation into revolutionary regenerative medicines.

Treatment of progressive multiple sclerosis with high-dose all-trans retinoic acid \u2013 no clear evidence of positive disease modifying effects

BackgroundAll-trans retinoic acid (ATRA) is an acid derivative of vitamin A which is discussed as a promising candidate to ameliorate the disease course of multiple sclerosis (MS) by immunomodulation or even by promoting regeneration in progressive MS. Here we report a patient who significantly improved for MS related disability following administration of chemotherapy including ATRA for mitoxantrone-related acute promyelocytic leukemia and assess the effect of high-dose ATRA in three additional patients with progressive MS.MethodsPatients with progressive MS who had failed previous therapies were treated with high-dose ATRA. Patients underwent clinical and routine laboratory monitoring. Additionally, PBMCs were analyzed by flow cytometry for lymphocyte subsets.ResultsATRA was well tolerated and no pathological laboratory abnormalities were observed. After initial mild (not statistically significant) improvement of EDSS and mean MSFC z-score, ongoing disease progression was observed. One patient subacutely experienced severe cognitive and motor worsening. Cerebral MRI revealed persistent gadolinium-enhancing lesions. Flow cytometric alterations of peripheral blood naïve, central memory and effector memory CD4 and CD8 T cells, B lymphocytes, plasma cells, memory B cells, plasmablasts and natural killer (NK) cells did not reach statistical significance.ConclusionsStand-alone therapy with ATRA did not ameliorate progressive MS in our limited cohort and we did not observe consistent alterations of T and B cell subsets. Intriguingly, application of ATRA may have caused marked disease exacerbation in one patient.

Treatment with Non-specific HDAC Inhibitors Administered after Disease Onset does not Delay Evolution in a Mouse Model of Progressive Multiple Sclerosis

Drugs able to efficiently counteract progression of multiple sclerosis (MS) are still an unmet need. Several lines of evidence indicate that histone deacetylase inhibitors (HDACi) are clinically-available epigenetic drugs that might be repurposed for immunosuppression in MS therapy. Here, we studied the effects of HDACi on disease evolution in myelin oligodendrocyte glycoprotein (MOG)-immunized NOD mice, an experimental model of progressive experimental autoimmune encephalomyelitis (PEAE). To obtain data of potential clinical relevance, the HDACi panobinostat, givinostat and entinostat were administered orally adopting a daily treatment protocol after disease onset. We report that the 3 drugs efficiently reduced in vitro lymphocyte proliferation in a dose-dependent manner. Notably, however, none of the drugs delayed evolution of PEAE or reduced lethality in NOD mice. In striking contrast with this, however, the lymphocyte proliferation response to MOG as well as Th1 and Th17 spinal cord infiltrates were significantly lower in animals exposed to the HDACi compared to those receiving vehicle. When put into a clinical context, for the first time data cast doubt on the relevance of HDACi to treatment of progressive MS (PMS). Also, our findings further indicate that, akin to PMS, neuropathogensis of PEAE in NOD mice becomes independent from autoimmunity, thereby corroborating the relevance of this model to experimental PMS research.

Astrocytes in the pathogenesis of multiple sclerosis

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS), and is designated as an intractable disease in Japan. It is characterized by dissemination of plaque-like sclerosis in space and time, accompanied with various symptoms corresponding to the CNS lesion site. Typically, neurological symptoms chronically progress accompanied with relapses and remissions, and there is still no curative therapy. A number of studies using MS specimen and the animal MS model experimental autoimmune encephalomyelitis (EAE) have shown that MS is an autoimmune disease that targets myelin sheath in the CNS. Autoreactive T cells and B cells play a central role in pathogenesis of MS. MS comprise relapsing-remitting MS and progressive MS, the latter accumulates clinical disability without relapse. Based on the importance of adaptive immunity, various disease-modifying drugs have been developed to treat relapsing-remitting MS. On the other hand, an effective treatment for progressive MS has not yet been established. Increasing evidence have been recognized glial cells as key components of MS immunopathology, in addition to innate immunity and adaptive immunity. However, molecular mechanisms of crosstalk between immune cells, glial cells and neurons remain to be elucidated. Here, we review MS pathology and recent advances in the disease-modifying therapy that efficiently reduce disease activity in relapsing-remitting MS and introduce an update of recent evidence that astrocyte is involved in the MS pathology with including our research analyzed in mouse EAE model.

Systematic approach to selecting licensed drugs for repurposing in the treatment of progressive multiple sclerosis

ObjectiveTo establish a rigorous, expert-led, evidence-based approach to the evaluation of licensed drugs for repurposing and testing in clinical trials of people with progressive multiple sclerosis (MS).MethodsWe long-listed licensed drugs...

Safety and efficacy of MD1003 (high-dose biotin) in patients with progressive multiple sclerosis (SPI2): a randomised, double-blind, placebo-controlled, phase 3 trial

There is an unmet need to develop therapeutic interventions directed at the neurodegeneration that underlies progression in multiple sclerosis. High-dose, pharmaceutical-grade biotin (MD1003) might enhance neuronal and oligodendrocyte energetics, resulting in improved cell function, repair, or survival. The MS-SPI randomised, double-blind, placebo-controlled study found that MD1003 improved disability outcomes over 12 months in patients with progressive multiple sclerosis. The SPI2 study was designed to assess the safety and efficacy of MD1003 in progressive forms of multiple sclerosis in a larger, more representative patient cohort. SPI2 was a randomised, double-blind, parallel-group, placebo-controlled trial done at 90 academic and community multiple sclerosis clinics across 13 countries. Patients were aged 18-65 years, had a diagnosis of primary or secondary progressive multiple sclerosis fulfilling the revised International Panel criteria and Lublin criteria, a Kurtzke pyramidal functional subscore of at least 2 (defined as minimal disability), an expanded disability status scale (EDSS) score of 3·5-6·5, a timed 25-foot walk (TW25) of less than 40 s, evidence of clinical disability progression, and no relapses in the 2 years before enrolment. Concomitant disease-modifying therapies were allowed. Patients were randomly assigned (1:1) by an independent statistician using an interactive web response system, with stratification by study site and disease history, to receive MD1003 (oral biotin 100 mg three times daily) or placebo. Participants, investigators, and assessors were masked to treatment assignment. The primary endpoint was a composite of the proportion of participants with confirmed improvement in EDSS or TW25 at month 12, confirmed at month 15, versus baseline. The primary endpoint was assessed in the intention-to-treat analysis set, after all participants completed the month 15 visit. Safety analyses included all participants who received at least one dose of MD1003. This trial is registered with ClinicalTrials.gov (NCT02936037) and the EudraCT database (2016-000700-29). From Feb 22, 2017, to June 8, 2018, 642 participants were randomly assigned MD1003 (n=326) or placebo (n=316). The double-blind, placebo-controlled phase of the study ended when the primary endpoint for the last-entered participant was assessed on Nov 15, 2019. The mean time in the placebo-controlled phase was 20·1 months (SD 5·3; range 15-27). For the primary outcome, 39 (12%) of 326 patients in the MD1003 group compared with 29 (9%) of 316 in the placebo group improved at month 12, with confirmation at month 15 (odds ratio 1·35 [95% CI 0·81-2·26]). Treatment-emergent adverse events occurred in 277 (84%) of 331 participants in the MD1003 group and in 264 (85%) of 311 in the placebo group. 87 (26%) of 331 participants in the MD1003 group and 82 (26%) of 311 participants in the placebo group had at least one serious treatment-emergent adverse event. One (<1%) person died in the MD1003 group and there were no deaths in the placebo group. Despite use of mitigation strategies, MD1003 led to inaccurate laboratory results for tests using biotinylated antibodies. This study showed that MD1003 did not significantly improve disability or walking speed in patients with progressive multiple sclerosis and thus, in addition to the potential of MD1003 for deleterious health consequences from interference of laboratory tests, MD1003 cannot be recommended for treatment of progressive multiple sclerosis. MedDay Pharmaceuticals.

The Role of Antibodies in the Pathogenesis of Multiple Sclerosis.

The presence of persistent intrathecal oligoclonal immunoglobulin G (IgG) bands (OCBs) and lesional IgG deposition are seminal features of multiple sclerosis (MS) disease pathology. Despite extensive investigations, the role of antibodies, the products of mature CD19+ B cells, in disease development is still controversial and under significant debate. Recent success of B cell depletion therapies has revealed that CD20+ B cells contribute to MS pathogenesis via both antigen-presentation and T-cell-regulation. However, the limited efficacy of CD20+ B cell depletion therapies for the treatment of progressive MS indicates that additional mechanisms are involved. In this review, we present findings suggesting a potential pathological role for increased intrathecal IgGs, the relation of circulating antibodies to intrathecal IgGs, and the selective elevation of IgG1 and IgG3 subclasses in MS. We propose a working hypothesis that circulating B cells and antibodies contribute significantly to intrathecal IgGs, thereby exerting primary and pathogenic effects in MS development. Increased levels of IgG1 and IgG3 antibodies induce potent antibody-mediated cytotoxicity to central nervous system (CNS) cells and/or reduce the threshold required for antigen-driven antibody clustering leading to optimal activation of immune responses. Direct proof of the pathogenic roles of antibodies in MS may provide opportunities for novel blood biomarker identification as well as strategies for the development of effective therapeutic interventions.