Cell-based therapeutic strategies for multiple sclerosis

Scolding, Neil; Pasquini, Marcelo C.; Reingold, Stephen C.; Cohen, Jeffrey A.

doi:10.1093/brain/awx154

Cited by 143 publications

(93 citation statements)

References 145 publications

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“…This data is in agreement with other studies and recent guidelines33 and confirms the important role of AHSCT as a therapeutic option for patients with RRMS. Data from the first phase III randomised controlled trial of AHSCT in MS (the MIST trial)34 showed a significant difference in NEDA rates between transplant and conventional MS DMT arms; however, the heterogeneity of the DMT arm means planned studies of AHSCT versus high efficacy immunotherapy are awaited with interest 35.…”

Section: Discussionsupporting

confidence: 93%

Prospective phase II clinical trial of autologous haematopoietic stem cell transplant for treatment refractory multiple sclerosis

Moore

Massey

Ford

et al. 2018

J Neurol Neurosurg Psychiatry

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BackgroundAutologous haematopoietic stem cell transplantation (AHSCT) has been explored as a therapeutic intervention in multiple sclerosis (MS) over the last two decades; however, prospective clinical trials of the most common myeloablative conditioning regimen, BEAM, are limited. Furthermore, patient selection, optimal chemotherapeutic regimen and immunological changes associated with disease response require ongoing exploration. We present the outcomes, safety and immune reconstitution (IR) of patients with active, treatment refractory MS.MethodsThis study was a single-centre, phase II clinical trial of AHSCT for patients with active relapsing remitting (RRMS) and secondary progressive MS (SPMS). Patients underwent AHSCT using BEAM (carmustine, etoposide, cytarabine, melphalan)+antithymocyte globulin chemotherapeutic regimen.OutcomesThe primary outcome was event-free survival (EFS); defined as no clinical or radiological relapses and no disability progression. Multiparameter flow cytometry was performed for evaluation of post-transplant IR in both MS and lymphoma patients receiving the same chemotherapy regimen.ResultsThirty-five patients (20 RRMS, 15 SPMS) completed AHSCT, with a median follow-up of 36 months (range 12–66). The median Expanded Disability Status Scores (EDSS) was 6 (2–7) and patients had failed a median of 4 (2–7) disease modifying therapies. 66% failed treatment with natalizumab. EFS at 3 years was 60%, (70% RRMS). Sustained improvement in EDSS was seen in 15 (44%) of patients. There was no treatment-related mortality. A sustained rise in CD39+ T regulatory cells, immunosuppressive CD56hi natural killer cells and ablation of proinflammatory mucosal-associated invariant T cells was seen for 12 months following AHSCT in patients with MS. These changes did not occur in patients with lymphoma receiving the same chemotherapy for AHSCT.ConclusionsThe EFS in our MS cohort is significantly greater than other high-efficacy immunosuppressive therapies and similar to other AHSCT studies despite a more heavily pretreated cohort.Trial registration numberACTRN12613000339752.

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Section: Discussionsupporting

confidence: 93%

Prospective phase II clinical trial of autologous haematopoietic stem cell transplant for treatment refractory multiple sclerosis

Moore

Massey

Ford

et al. 2018

J Neurol Neurosurg Psychiatry

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“…It is encouraging to note that such studies are now underway. Cell-based therapies include depletion of the immune system via immunoablation, followed by mesenchymal and related stem cell transplantation, autologous hematopoietic stem cell transplantation, transplantation of oligodendrocyte progenitor cells, and introduction of endogenous stem cells followed by enhancement of their reparative capabilities [85]. Although these are potentially breakthrough treatment approaches, there are methodological and ethical challenges in designing such studies, and our understanding of potential benefits and safety concerns is limited, thereby relegating these approaches to aggressive or hard-to-treat MS for which treatments are desperately needed but few are available.…”

Section: Cell-based Immunotherapiesmentioning

confidence: 99%

Epstein–Barr Virus in Multiple Sclerosis: Theory and Emerging Immunotherapies

Bar‐Or

Pender

Khanna

et al. 2020

Trends in Molecular Medicine

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149

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New treatments for multiple sclerosis (MS) focused on B cells have created an atmosphere of excitement in the MS community. B cells are now known to play a major role in disease, demonstrated by the highly impactful effect of a B cell-depleting antibody on controlling MS. The idea that a virus may play a role in the development of MS has a long history and is supported mostly by studies demonstrating a link between B cell-tropic Epstein-Barr virus (EBV) and disease onset. Efforts to develop antiviral strategies for treating MS are underway. Although gaps remain in our understanding of the etiology of MS, the role, if any, of viruses in propagating pathogenic immune responses deserves attention. HighlightsClinical studies show that depletion of B cells reduces disease burden in both relapsing-remitting and progressive multiple sclerosis (MS) patients.

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“…Mesenchymal stem cells (MSCs), which have been isolated from bone marrow, umbilical cord, dental pulp, and a diversity of other tissues, have the ability of differentiating into tissue‐specific lineages . An increasing number of studies have demonstrated promising applications of MSCs in regenerative medicine and tissue engineering to repair and regenerate damaged or lost tissues due to diseases and traumatic injuries and, nonetheless, translational uses of MSCs remain inefficacious, in part due to their limited capability of migrating and homing . Thus, gaining insights into the mechanisms regulating MSC migration can provide useful information for developing novel strategies to prepare MSCs for clinical applications and improve the efficacy of MSC‐based therapies as well as evolving a better understanding of the contentious MSC biology .…”

Section: Introductionmentioning

confidence: 99%

Chemical activation of the Piezo1 channel drives mesenchymal stem cell migration via inducing ATP release and activation of P2 receptor purinergic signaling

Mousawi

Peng

et al. 2020

Stem Cells

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In this study, we examined the Ca2+‐permeable Piezo1 channel, a newly identified mechanosensing ion channel, in human dental pulp‐derived mesenchymal stem cells (MSCs) and hypothesized that activation of the Piezo1 channel regulates MSC migration via inducing ATP release and activation of the P2 receptor purinergic signaling. The Piezo1 mRNA and protein were readily detected in hDP‐MSCs from multiple donors and, consistently, brief exposure to Yoda1, the Piezo1 channel‐specific activator, elevated intracellular Ca2+ concentration. Yoda1‐induced Ca2+ response was inhibited by ruthenium red or GsMTx4, two Piezo1 channel inhibitors, and also by Piezo1‐specific siRNA. Brief exposure to Yoda1 also induced ATP release. Persistent exposure to Yoda1 stimulated MSC migration, which was suppressed by Piezo1‐specific siRNA, and also prevented by apyrase, an ATP scavenger, or PPADS, a P2 generic antagonist. Furthermore, stimulation of MSC migration induced by Yoda1 as well as ATP was suppressed by PF431396, a PYK2 kinase inhibitor, or U0126, an inhibitor of the mitogen‐activated protein kinase MEK/ERK signaling pathway. Collectively, these results suggest that activation of the Piezo1 channel stimulates MSC migration via inducing ATP release and subsequent activation of the P2 receptor purinergic signaling and downstream PYK2 and MEK/ERK signaling pathways, thus revealing novel insights into the molecular and signaling mechanisms regulating MSC migration. Such findings provide useful information for evolving a full understanding of MSC migration and homing and developing strategies to improve MSC‐based translational applications.

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Cell-based therapeutic strategies for multiple sclerosis

Cited by 143 publications

References 145 publications

Prospective phase II clinical trial of autologous haematopoietic stem cell transplant for treatment refractory multiple sclerosis

Prospective phase II clinical trial of autologous haematopoietic stem cell transplant for treatment refractory multiple sclerosis

Epstein–Barr Virus in Multiple Sclerosis: Theory and Emerging Immunotherapies

Chemical activation of the Piezo1 channel drives mesenchymal stem cell migration via inducing ATP release and activation of P2 receptor purinergic signaling

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