Remyelination: what are the prospects for regenerative therapies in multiple sclerosis?

2021 ◽  
Author(s):  
Jonathan D. Moore
Keyword(s):  
Multiple Sclerosis ◽  
Immune System ◽  
Unmet Need ◽  
Good Control ◽  
Small Companies ◽  
Myelin Sheaths ◽  
Working Age ◽  
Regenerative Therapies ◽  
Neuroprotective Therapies

Multiple sclerosis (MS) involves the immune system attacking the myelin sheaths surrounding axons and is a major cause of disability in working-age adults. Various approved therapies now provide reasonably good control over MS neuroinflammation, but none have a pronounced impact on the neurodegeneration associated with the disease. One prominent approach to fulfilling the unmet need for neuroprotective therapies, is the search for agents that promote ‘remyelination', namely the generation of new oligodendrocytes that can form replacement myelin sheaths around denuded axons. In this article, I discuss some emerging targets for remyelinating therapies, mainly being pursued by recently formed small companies translating academic findings.

scholarly journals Multiple Sclerosis-Secondary Progressive Multi-Arm Randomisation Trial (MS-SMART): a multiarm phase IIb randomised, double-blind, placebo-controlled clinical trial comparing the efficacy of three neuroprotective drugs in secondary progressive multiple sclerosis

BMJ Open ◽  
2018 ◽  
Vol 8 (8) ◽  
pp. e021944 ◽  
Author(s):  
Peter Connick ◽  
Floriana De Angelis ◽  
Richard A Parker ◽  
Domenico Plantone ◽  
Anisha Doshi ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Unmet Need ◽  
Dropout Rate ◽  
Analysis Of Covariance ◽  
Controlled Clinical Trial ◽  
Imaging Data ◽  
Secondary Progressive ◽  
Link Type ◽  
Oral Agents ◽  
Neuroprotective Therapies

IntroductionThe major unmet need in multiple sclerosis (MS) is for neuroprotective therapies that can slow (or ideally stop) the rate of disease progression. The UK MS Society Clinical Trials Network (CTN) was initiated in 2007 with the purpose of developing a national, efficient, multiarm trial of repurposed drugs. Key underpinning work was commissioned by the CTN to inform the design, outcome selection and drug choice including animal models and a systematic review. This identified seven leading oral agents for repurposing as neuroprotective therapies in secondary progressive MS (SPMS). The purpose of the Multiple Sclerosis-Secondary Progressive Multi-Arm Randomisation Trial (MS-SMART) will be to evaluate the neuroprotective efficacy of three of these drugs, selected with distinct mechanistic actions and previous evidence of likely efficacy, against a common placebo arm. The interventions chosen were: amiloride (acid-sensing ion channel antagonist); fluoxetine (selective serotonin reuptake inhibitor) and riluzole (glutamate antagonist).Methods and analysisPatients with progressing SPMS will be randomised 1:1:1:1 to amiloride, fluoxetine, riluzole or matched placebo and followed for 96 weeks. The primary outcome will be the percentage brain volume change (PBVC) between baseline and 96 weeks, derived from structural MR brain imaging data using the Structural Image Evaluation, using Normalisation, of Atrophy method. With a sample size of 90 per arm, this will give 90% power to detect a 40% reduction in PBVC in any active arm compared with placebo and 80% power to detect a 35% reduction (analysing by analysis of covariance and with adjustment for multiple comparisons of three 1.67% two-sided tests), giving a 5% overall two-sided significance level. MS-SMART is not powered to detect differences between the three active treatment arms. Allowing for a 20% dropout rate, 110 patients per arm will be randomised. The study will take place at Neuroscience centres in England and Scotland.Ethics and disseminationMS-SMART was approved by the Scotland A Research Ethics Committee on 13 January 2013 (REC reference: 13/SS/0007). Results of the study will be submitted for publication in a peer-reviewed journal.Trial registration numbersNCT01910259; 2012-005394-31;ISRCTN28440672.

scholarly journals Elucidating distinct clinico-radiologic signatures in the borderland between neuromyelitis optica and multiple sclerosis

2021 ◽  
Author(s):  
Maciej Juryńczyk ◽  
Elżbieta Klimiec-Moskal ◽  
Yazhuo Kong ◽  
Samuel Hurley ◽  
Silvia Messina ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Neuromyelitis Optica ◽  
Unmet Need ◽  
Transverse Myelitis ◽  
Overlap Syndrome ◽  
Brain Lesions ◽  
Central Vein ◽  
Normal Brain ◽  
Group 4 ◽  
Group 2

Abstract Background Separating antibody-negative neuromyelitis optica spectrum disorders (NMOSD) from multiple sclerosis (MS) in borderline cases is extremely challenging due to lack of biomarkers. Elucidating different pathologies within the likely heterogenous antibody-negative NMOSD/MS overlap syndrome is, therefore, a major unmet need which would help avoid disability from inappropriate treatment. Objective In this study we aimed to identify distinct subgroups within the antibody-negative NMOSD/MS overlap syndrome. Methods Twenty-five relapsing antibody-negative patients with NMOSD features underwent a prospective brain and spinal cord MRI. Subgroups were identified by an unsupervised algorithm based on pre-selected NMOSD/MS discriminators. Results Four subgroups were identified. Patients from Group 1 termed “MS-like” (n = 6) often had central vein sign and cortical lesions (83% and 67%, respectively). All patients from Group 2 (“spinal MS-like”, 8) had short-segment myelitis and no MS-like brain lesions. Group 3 (“classic NMO-like”, 6) had high percentage of bilateral optic neuritis and longitudinally extensive transverse myelitis (LETM, 80% and 60%, respectively) and normal brain appearance (100%). Group 4 (“NMO-like with brain involvement”, 5) typically had a history of NMOSD-like brain lesions and LETM. When compared with other groups, Group 4 had significantly decreased fractional anisotropy in non-lesioned tracts (0.46 vs. 0.49, p = 0.003) and decreased thalamus volume (0.84 vs. 0.98, p = 0.04). Conclusions NMOSD/MS cohort contains distinct subgroups likely corresponding to different pathologies and requiring tailored treatment. We propose that non-conventional MRI might help optimise diagnosis in these challenging patients.

Recent advances on immunosuppressive drugs and remyelination enhancers for the treatment of multiple sclerosis

2021 ◽  
Vol 27 ◽  
Author(s):  
Jennifer Cadenas-Fernández ◽  
Pablo Ahumada-Pascual ◽  
Luis Sanz Andreu ◽  
Ana Velasco
Keyword(s):  
Multiple Sclerosis ◽  
Intracellular Signaling ◽  
Demyelinating Disease ◽  
Lipid Synthesis ◽  
Immunosuppressive Drugs ◽  
Nerve Fibers ◽  
Myelin Sheaths ◽  
Demyelinating Lesions ◽  
The Central Nervous System ◽  
Lipid Structures

: Mammalian nervous systems depend crucially on myelin sheaths covering the axons. In the central nervous system, myelin sheaths consist of lipid structures which are generated from the membrane of oligodendrocytes (OL). These sheaths allow fast nerve transmission, protect axons and provide them metabolic support. In response to specific traumas or pathologies, these lipid structures can be destabilized and generate demyelinating lesions. Multiple sclerosis (MS) is an example of a demyelinating disease in which the myelin sheaths surrounding the nerve fibers of the brain and spinal cord are damaged. MS is the leading cause of neurological disability in young adults in many countries, and its incidence has been increasing in recent decades. Related to its etiology, it is known that MS is an autoimmune and inflammatory CNS disease. However, there are no effective treatments for this disease and the immunomodulatory therapies that currently exist have proven limited success since they only delay the progress of the disease. Nowadays, one of the main goals in the MS research is to find treatments which allows the recovery of neurological disabilities due to demyelination. To this end, different approaches, such as modulating intracellular signaling or regulating the lipid metabolism of OLs, are being considered. Here, in addition to immunosuppressive or immunomodulatory drugs that reduce the immune response against myelin sheaths, we review a diverse group of drugs that promotes endogenous remyelination in MS patients and whose use may be interesting as potential therapeutic agents in MS disease. To this end, we compile specific treatments against MS that are currently in the market with remyelination strategies which have entered into human clinical trials for future reparative MS therapies. The method used in this study is a systematic literature review on PubMed, Web of Science and Science Direct databases up to May 31, 2020. To narrow down the search results in databases, more specific keywords, such as, “myelin sheath”, “remyelination”, “demyelination”, “oligodendrocyte” and “lipid synthesis” were used to focus the search. We favoured papers published after January, 2015, but did not exclude earlier seminal papers.

Review of neurological rehabilitation for Multiple Sclerosis in the British Military

2021 ◽  
pp. bmjmilitary-2021-001852
Author(s):  
Oliver O'Sullivan ◽  
L Allsopp ◽  
J Mitchell ◽  
L Price ◽  
K Tourle ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Armed Forces ◽  
Medical Rehabilitation ◽  
Neurological Rehabilitation ◽  
Patient Support ◽  
Rehabilitation Centre ◽  
Occupational Outcomes ◽  
British Military ◽  
Working Age

Multiple sclerosis (MS) is a progressive neurological disorder, classically presenting in working age adults, including those in the Armed Forces. The Defence Medical Rehabilitation Centre (DMRC) Stanford Hall offers vocationally focused neurorehabilitation services for service personnel (SP) with MS, with the goal to minimise disability, maximise independence and remain able to work.This paper has two aims. First, it briefly provides a clinical update of MS, focusing on pathology, presentation, diagnosis and management. Finally, it will describe the role of DMRC and data from the last decade in the management of MS.Our findings suggest not all SP with MS are being referred to DMRC, and some of those who do have significant delays, potentially impacting on patient support, symptom management and occupational outcomes. It is hoped that this paper will improve awareness and recognition of MS for Armed Forces personnel.

scholarly journals Infectious and Noninfectious Granulomatosis in Patient with Multiple Sclerosis: Diagnostic Dilemmas and Followup

2014 ◽  
Vol 2014 ◽  
pp. 1-6
Author(s):  
Jelena Paovic ◽  
Predrag Paovic ◽  
Vojislav Sredovic
Keyword(s):  
Multiple Sclerosis ◽  
Immune System ◽  
Pulmonary Tuberculosis ◽  
Cataract Surgery ◽  
Systemic Infection ◽  
Neurological Manifestations ◽  
Initial Attack ◽  
Mri Findings ◽  
Retrobulbar Neuritis ◽  
Preoperative Procedures

Patient was followed up over the course of 30 years. In 1978, after severe systemic infection followed by fever, pulmonary edema, and numerous neurological manifestations, patient was differentially diagnosed with apoplectic form of multiple sclerosis (MS), which was confirmed a year later via neurological and MRI findings. Approximately 20 years following the initial attack, sarcoidosis was diagnosed during the regular preoperative procedures required for cataract surgery. As consequence of lower immune system, infectious granulomatosis in form of pulmonary tuberculosis developed. Ophthalmological findings revealed bilateral retrobulbar neuritis (RBN) approximately six years after initial attack. This developed into total uveitis with retinal periphlebitis and anterior granulomatous uveitis—all of which are clinically similar in both MS and sarcoidosis.

Health, disability, and life insurance experiences of working-age persons with multiple sclerosis

2007 ◽  
Vol 13 (4) ◽  
pp. 534-546 ◽  
Author(s):  
LI Iezzoni ◽  
L. Ngo
Keyword(s):  
Multiple Sclerosis ◽  
Health Care ◽  
Health Insurance ◽  
Life Insurance ◽  
College Education ◽  
Employment Decisions ◽  
Public Programs ◽  
Considerable Difficulty ◽  
Telephone Interviews ◽  
Working Age

Working-age Americans with multiple sclerosis (MS) may face considerable financial insecurities when they become unable to work and lack the health, disability, and life insurance typically offered through employers. In order to estimate the rates of having these insurance policies, as well as how insurance status affects reports of financial stress, we conducted half-hour telephone interviews with 983 working-age persons across the US, who reported being diagnosed with MS. The interviews occurred from May through November 2005, and among the sampled individuals contacted and confirmed eligible, 93.2% completed the interview. The study population was largely female (78.9%), Caucasian (86.4%), married (68.6%), with at least some college education (71.5%), and unemployed (60.2%). Overall, 96.3% had some health insurance (40.3% with public health insurance, primarily Medicare), 56.7% had long-term disability insurance (36.4% with public programs), and 68.3% had life insurance. Notably, 27.4% indicated that, since being diagnosed with MS, health insurance concerns had significantly affected employment decisions. In addition, 16.4% reported considerable difficulty paying for health care, 27.4% put off or postponed seeking needed health care because of costs, and 22.3% delayed filling prescriptions, skipped medication doses, or split pills because of costs. Overall, 26.6% reported considerable worries about affording even basic necessities, such as food, utilities, and housing. Multiple Sclerosis 2007; 13: 534-546. http://msj.sagepub.com

Vaccination opportunities in multiple sclerosis patients treated with cladribine tablets

2021 ◽  
Vol 20 ◽  
Author(s):  
Lucia Moiola ◽  
Agostino Riva ◽  
Ferdinando Nicoletti ◽  
Antonio Uccelli ◽  
Marco Salvetti ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Immune System ◽  
Mechanism Of Action ◽  
Vaccination Campaign ◽  
Humoral Response ◽  
Focused Attention ◽  
Vulnerable Patients ◽  
Mass Vaccination Campaign ◽  
Multiple Sclerosis Patients ◽  
Vaccination Campaigns

: The COVID-19 pandemic and the mass vaccination campaign highlighted the situation of the most vulnerable patients. In this work, we focused attention on patients who have Multiple Sclerosis (MS), particularly in treatment with cladribine tablets, trying to understand if and when it is possible to administer the vaccine successfully. Considering the innovative topic, we reviewed the existing literature with an analysis of the experiences also related to other vaccinations, including influenza and VZV, and very recent data from countries with vaccination campaigns already advanced. Overall, we have taken into account the mechanism of action, the pharmacokinetic/pharmacodynamic of cladribine and the changes in the immune system after its administration, together with the preliminary data about the humoral response to influenza, VZV and SARS-CoV-2 vaccinations in cladribine treated patients. In conclusion, data showed that the use of cladribine tablets seems to permit flexibility regarding vaccination timing and we suggest that vaccination in those patients should be safe and effective.

scholarly journals Suppression of the Peripheral Immune System Limits the Central Immune Response Following Cuprizone-Feeding: Relevance to Modelling Multiple Sclerosis

Cells ◽  
2019 ◽  
Vol 8 (11) ◽  
pp. 1314 ◽  
Author(s):  
Sen ◽  
Almuslehi ◽  
Gyengesi ◽  
Myers ◽  
Shortland ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Immune Response ◽  
Immune System ◽  
Adaptive Immune System ◽  
Synaptic Function ◽  
Adaptive Immune ◽  
Splenic Atrophy ◽  
The Impact ◽  
The Brain ◽  
Inside Out

Cuprizone (CPZ) preferentially affects oligodendrocytes (OLG), resulting in demyelination. To investigate whether central oligodendrocytosis and gliosis triggered an adaptive immune response, the impact of combining a standard (0.2%) or low (0.1%) dose of ingested CPZ with disruption of the blood brain barrier (BBB), using pertussis toxin (PT), was assessed in mice. 0.2% CPZ(±PT) for 5 weeks produced oligodendrocytosis, demyelination and gliosis plus marked splenic atrophy (37%) and reduced levels of CD4 (44%) and CD8 (61%). Conversely, 0.1% CPZ(±PT) produced a similar oligodendrocytosis, demyelination and gliosis but a smaller reduction in splenic CD4 (11%) and CD8 (14%) levels and no splenic atrophy. Long-term feeding of 0.1% CPZ(±PT) for 12 weeks produced similar reductions in CD4 (27%) and CD8 (43%), as well as splenic atrophy (33%), as seen with 0.2% CPZ(±PT) for 5 weeks. Collectively, these results suggest that 0.1% CPZ for 5 weeks may be a more promising model to study the ‘inside-out’ theory of Multiple Sclerosis (MS). However, neither CD4 nor CD8 were detected in the brain in CPZ±PT groups, indicating that CPZ-mediated suppression of peripheral immune organs is a major impediment to studying the ‘inside-out’ role of the adaptive immune system in this model over long time periods. Notably, CPZ(±PT)-feeding induced changes in the brain proteome related to the suppression of immune function, cellular metabolism, synaptic function and cellular structure/organization, indicating that demyelinating conditions, such as MS, can be initiated in the absence of adaptive immune system involvement.

scholarly journals Does Resetting the Immune System Fix Multiple Sclerosis?

2019 ◽  
Vol 47 (1) ◽  
pp. 1-10
Author(s):  
Gauruv Bose ◽  
Simon D. X. Thebault ◽  
Harold L. Atkins ◽  
Mark S. Freedman
Keyword(s):  
Multiple Sclerosis ◽  
Immune System ◽  
Therapeutic Option ◽  
Disease Course ◽  
Phase Ii Trials ◽  
Durable Response ◽  
Treatment Protocols ◽  
Hematopoietic Stem ◽  
Aggressive Disease ◽  
Conditioning Regimens

Abstract:Multiple sclerosis is the leading non-traumatic cause of disability in young adults, affecting up to 100,000 Canadians. This chronic inflammatory and neurodegenerative disease of the central nervous system leads to irreversible neurologic disability if inadequately controlled. Though many current medications are available that reduce inflammatory damage, most patients continue to show some evidence of disease activity and accrue disability. In this review, we discuss the role of immune ablation followed by autologous hematopoietic stem cell transplantation (AHSCT), a therapeutic option for select patients with a more aggressive disease course. By “resetting” the immune system with a variety of ablative conditioning regimens, followed by immune reconstitution, this therapy has shown a durable response in halting evidence of inflammatory activity in most patients, without the need for continued disease-modifying therapies (DMT). Since the introduction of this therapy, there have been advances in patient selection and supportive care, such that morbidity has significantly declined and treatment-related mortality is minimized. Recent phase-II trials have shown excellent results in efficacy and safety of AHSCT; however, challenges exist which require ongoing study. The future challenges include comparing the variety of AHSCT conditioning regimens with each other as well as with existing highly effective DMT; identifying patients with an aggressive disease course through novel biomarkers who may benefit the most from AHSCT; and surveillance of long-term outcomes of different treatment protocols. In select patients, replacing the immune system with AHSCT holds promise of fundamentally altering the trajectory of their aggressive disease course.

scholarly journals The Potential of Computational Modeling to Predict Disease Course and Treatment Response in Patients with Relapsing Multiple Sclerosis

Cells ◽  
2020 ◽  
Vol 9 (3) ◽  
pp. 586 ◽  
Author(s):  
Francesco Pappalardo ◽  
Giulia Russo ◽  
Marzio Pennisi ◽  
Giuseppe Alessandro Parasiliti Palumbo ◽  
Giuseppe Sgroi ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Immune System ◽  
Computational Modeling ◽  
Response To Treatment ◽  
Oligoclonal Bands ◽  
Host Immune System ◽  
Immunological Parameters ◽  
Disease Modifying Drugs ◽  
Magnetic Resonance Imaging Mri ◽  
Relapsing Multiple Sclerosis

As of today, 20 disease-modifying drugs (DMDs) have been approved for the treatment of relapsing multiple sclerosis (MS) and, based on their efficacy, they can be grouped into moderate-efficacy DMDs and high-efficacy DMDs. The choice of the drug mostly relies on the judgment and experience of neurologists and the evaluation of the therapeutic response can only be obtained by monitoring the clinical and magnetic resonance imaging (MRI) status during follow up. In an era where therapies are focused on personalization, this study aims to develop a modeling infrastructure to predict the evolution of relapsing MS and the response to treatments. We built a computational modeling infrastructure named Universal Immune System Simulator (UISS), which can simulate the main features and dynamics of the immune system activities. We extended UISS to simulate all the underlying MS pathogenesis and its interaction with the host immune system. This simulator is a multi-scale, multi-organ, agent-based simulator with an attached module capable of simulating the dynamics of specific biological pathways at the molecular level. We simulated six MS patients with different relapsing–remitting courses. These patients were characterized based on their age, sex, presence of oligoclonal bands, therapy, and MRI lesion load at the onset. The simulator framework is made freely available and can be used following the links provided in the availability section. Even though the model can be further personalized employing immunological parameters and genetic information, we generated a few simulation scenarios for each patient based on the available data. Among these simulations, it was possible to find the scenarios that realistically matched the real clinical and MRI history. Moreover, for two patients, the simulator anticipated the timing of subsequent relapses, which occurred, suggesting that UISS may have the potential to assist MS specialists in predicting the course of the disease and the response to treatment.

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