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Scientists building on earlier research into stem cells have managed to halt multiple sclerosis (MS)
Scientists building on earlier research into stem cells have managed to halt multiple sclerosis (MS) in a clinical trial, but the treatment is not suitable for patients with an advanced stage of the disease.
In 10 seconds? A large trial involving MS patients found that stem cell therapy was stopping relapses and disease progress in almost all participants — the best result yet in any MS-related trial — and the benefits lasted up to 3 years.
What happened? Researchers tested whether wiping out a patient’s immune system and rebuilding it with stem cells could stop and reverse MS — which is what happened for most of the patients in the treatment group. Of the 52 study participants given the ‘stem cell reboot’, only one of them relapsed a year later.
How did they do it? Knowing that MS damages nerves due to an undesired overreaction in the patients’ immune system, scientists used chemotherapy to firstly wipe out their immune system. They then injected blood-cell-generating stem cells harvested from the patients’ own bone marrow by drip-feed into the bloodstream, achieving a ‘clean re-install’ of their immune system.
So, the problem went away? Seems so! One year after the treatment almost everyone was symptom-free. Three years later still, 94% of the group was still relapse-free. To compare, in the control group, 60% of people suffered an MS relapse in same period.
And how did the patients feel? The trial — and similar treatments elsewhere — were cathartic for many. One patient described receiving the stem cells as a ‘rebirth’; another left behind her wheelchair, started a family and referred to her symptoms as a ‘bad dream’.
Is this treatment too good to be true? The results of this trial were unveiled at a conference this week and the scientific community is now waiting to review and confirm the research data.
As to the risk, a small number of patients died from infections that pounced after the initial chemotherapy weakened their immune system.
Additionally, the treatment is not applicable for secondary-progressive MS patients, whose neural damage is too far advanced, but offers hope to many others.
Abstract: The availability of multiple disease-modifying medications with regulatory approval to treat multiple sclerosis illustrates the substantial progress made in therapy of the disease. However, all are only partially effective in preventing inflammatory tissue damage in the central nervous system and none directly promotes repair. Cell-based therapies, including immunoablation followed by autologous haematopoietic stem cell transplantation, mesenchymal and related stem cell transplantation, pharmacologic manipulation of endogenous stem cells to enhance their reparative capabilities, and transplantation of oligodendrocyte progenitor cells, have generated substantial interest as novel therapeutic strategies for immune modulation, neuroprotection, or repair of the damaged central nervous system in multiple sclerosis. Each approach has potential advantages but also safety concerns and unresolved questions. Moreover, clinical trials of cell-based therapies present several unique methodological and ethical issues. We summarize here the status of cell-based therapies to treat multiple sclerosis and make consensus recommendations for future research and clinical trials.
Pub.: 21 Oct '17, Pinned: 22 Mar '18
Abstract: Experimental autoimmune encephalomyelitis (EAE) in rats through immunization with guinea pig spinal cord homogenate (GPSCH) produces a chronic disease with a relapsing pattern such as multiple sclerosis (MS) in humans. In previous studies, the immunomodulatory benefits of mesenchymal stem cells (MSCs) and nicotine have already been determined. Thus, this research was conducted to assess the additional benefits of the combination therapy of MSCs and nicotine in a rat model of MS. EAE was induced by GPSCH and complete Freund's adjuvant (CFA) in female Wistar rats. The therapies were initiated at day 12 post-immunization (p.i.), when the rats developed a neurological disability score. The symptoms were recorded daily until day 33, when the rats were sacrificed. Finally, the splenocytes were evaluated by Enzyme-linked immunosorbent assay (ELISA) for cytokine production. The therapeutic treatment in the EAE rats with a combination of MSCs and nicotine exhibited a more desirable outcome, causing the regression of the average mean clinical score and neuropathological features to be more favorable than the treatment with either therapy alone. The combination therapy led to a significant reduction in the cumulative disease disability from day 21. For the EAE rats treated with nicotine and MSCs, this period was started from day 22 and 28 p.i., respectively. Besides the increase in the levels of IL-10, the combined therapy significantly reduced the splenocytes production of pro-inflammatory IL-17 as well as TNF-α more profoundly than either of the medications alone. In conclusion, the combination of MSCs and nicotine can be suggested as a promising strategy for further MS therapeutics improvement.
Pub.: 04 Nov '17, Pinned: 22 Mar '18
Abstract: The presence of neurotrophic factors is critical for regeneration of neural lesions. Here, we transplanted combination of neurotrophic factor secreting cells (NTF-SCs) and human adipose derived stem cells (hADSCs) into a lysolecithin model of multiple sclerosis (MS) and determined the myelinization efficiency of these cells.In this experimental study, 50 adult rats were randomly divided into five groups: control, lysolecithin, vehicle, hADSCs transplantation and NTF-SCs/ hADSCs co-transplantation group. Focal demyelization was induced by lysolecithin injection into the spinal cord. In order to assess motor functions, all rats were scored weekly with a standard experimental autoimmune encephalomyelitis scoring scale before and after cell transplantation. Four weeks after cell transplantation, the extent of demyelination and remyelination were examined with Luxol Fast Blue (LFB) staining. Also, immunofluorescence method was used for evaluation of oligodendrocyte differentiation markers including; myelin basic protein (MBP) and Olig2 in the lesion area.Histological study show somewhat remyelinzation in cell transplantation groups related to others. In addition, the immunofluorescence results indicated that the MBP and Olig2 positive labeled cells were significantly higher in co-cell transplantation group than hADSCs group (P<0.05). Also, outcome of motor functional test showed significant improvement function in cell transplantation groups, as compared to the others (P<0.01).Our results indicated that the remyelinization process in co-cell transplantation group was better than other groups. Thus, NTF-SCs/ hADSCs transplantation can be proper candidate for cell based therapy in neurodegenerative diseases, such as MS.
Pub.: 09 Jan '18, Pinned: 22 Mar '18
Abstract: Multiple sclerosis (MS) is the most prevalent and progressive autoimmune disease that affects the central nervous system, and currently, no drug is available for the treatment. Stem cell therapy has received substantial attention in MS treatment. Recently, we demonstrated the immunosuppressive effects of mesenchymal stem cells derived from neural crest-originated human periodontal ligament tissue (hPDLSCs) in an in vivo model of MS. In the present study, we comparatively investigated the stemness properties of hPDLSCs derived from healthy donors and relapsing-remitting MS patients. Stem cell marker expression, cell proliferation, and differentiation capacity were studied. We found that both donor- and MS patient-derived hPDLSCs at early passage 2 showed similar expression of surface antigen markers and cell proliferation rate. Significant level of osteogenic, adipogenic, chondrogenic, and neurogenic differentiation capacities was observed in both donor- and MS patient-derived hPDLSCs. Interestingly, these cells maintained the stemness properties even at late passage 15. Senescence markers p16 and p21 expression was considerably enhanced in passage 15. Our results propose that hPDLSCs may serve as simple and potential autologous stem cell niche, which may help in personalized stem cell therapy for MS patients.
Pub.: 02 Feb '18, Pinned: 22 Mar '18
Abstract: Multiple sclerosis (MS) is an immune-mediated demyelinating disease of the central nervous system and is one of the leading causes of disability in young adults. Cell therapy is emerging as a therapeutic strategy to promote repair and regeneration in patients with disability associated with progressive MS.We conducted a phase I open-label clinical trial investigating the safety and tolerability of autologous bone marrow mesenchymal stem cell-derived neural progenitor (MSC-NP) treatment in 20 patients with progressive MS. MSC-NPs were administered intrathecally (IT) in three separate doses of up to 1 × 10cells per dose, spaced three months apart. The primary endpoint was to assess safety and tolerability of the treatment. Expanded disability status scale (EDSS), timed 25-ft walk (T25FW), muscle strength, and urodynamic testing were used to evaluate treatment response. This trial is registered with ClinicalTrials.gov, number NCT01933802.IT MSC-NP treatment was safe and well tolerated. The 20 enrolled subjects completed all 60 planned treatments without serious adverse effects. Minor adverse events included transient fever and mild headaches usually resolving in <24 h. Post-treatment disability score analysis demonstrated improved median EDSS suggesting possible efficacy. Positive trends were more frequently observed in the subset of SPMS patients and in ambulatory subjects (EDSS ≤ 6.5). In addition, 70% and 50% of the subjects demonstrated improved muscle strength and bladder function, respectively, following IT MSC-NP treatment.The possible reversal of disability that was observed in a subset of patients warrants a larger phase II placebo-controlled study to establish efficacy of IT MSC-NP treatment in patients with MS.The Damial Foundation.
Pub.: 17 Feb '18, Pinned: 22 Mar '18
Abstract: Multiple sclerosis (MS), a complex disorder of the central nervous system (CNS), is characterized with axonal loss underlying long-term progressive disability. Currently available therapies for its management are able to slow down the progression but fail to treat it completely. Moreover, these therapies are associated with major CNS and cardiovascular adverse events, and prolonged use of these treatments may cause life-threatening diseases. Recent research has shown that cellular therapies hold a potential for CNS repair and may be able to provide protection from inflammatory damage caused after injury. Human embryonic stem cell (hESC) transplantation is one of the promising cell therapies; hESCs play an important role in remyelination and help in preventing demylenation of the axons. In this study, an overview of the current knowledge about the unique properties of hESC and their comparison with other cell therapies has been presented for the treatment of patients with MS.
Pub.: 28 Feb '18, Pinned: 22 Mar '18
Abstract: In this issue of Cell Stem Cell, Peruzzotti-Jametti et al. (2018) demonstrate how neural stem cells, transplanted in a mouse model of multiple sclerosis, respond to extracellular succinate and modulate neuroinflammation by releasing anti-inflammatory prostaglandin E2 and scavenging succinate. This mechanism reduces CNS damage and ameliorates motor impairment. Copyright © 2018 Elsevier Inc. All rights reserved.
Pub.: 03 Mar '18, Pinned: 22 Mar '18
Abstract: Publication date: Available online 22 February 2018 Source:Cell Stem Cell Author(s): Luca Peruzzotti-Jametti, Joshua D. Bernstock, Nunzio Vicario, Ana S.H. Costa, Chee Keong Kwok, Tommaso Leonardi, Lee M. Booty, Iacopo Bicci, Beatrice Balzarotti, Giulio Volpe, Giulia Mallucci, Giulia Manferrari, Matteo Donegà, Nunzio Iraci, Alice Braga, John M. Hallenbeck, Michael P. Murphy, Frank Edenhofer, Christian Frezza, Stefano Pluchino Neural stem cell (NSC) transplantation can influence immune responses and suppress inflammation in the CNS. Metabolites, such as succinate, modulate the phenotype and function of immune cells, but whether and how NSCs are also activated by such immunometabolites to control immunoreactivity and inflammatory responses is unclear. Here, we show that transplanted somatic and directly induced NSCs ameliorate chronic CNS inflammation by reducing succinate levels in the cerebrospinal fluid, thereby decreasing mononuclear phagocyte (MP) infiltration and secondary CNS damage. Inflammatory MPs release succinate, which activates succinate receptor 1 (SUCNR1)/GPR91 on NSCs, leading them to secrete prostaglandin E2 and scavenge extracellular succinate with consequential anti-inflammatory effects. Thus, our work reveals an unexpected role for the succinate-SUCNR1 axis in somatic and directly induced NSCs, which controls the response of stem cells to inflammatory metabolic signals released by type 1 MPs in the chronically inflamed brain. Graphical abstract Teaser Peruzzotti-Jametti et al. demonstrate that somatic and directly induced brain stem cells injected into the cerebrospinal fluid of mice with experimental multiple sclerosis ameliorate chronic neuroinflammation. Grafted stem cells use SUCNR1 to decrease the inflammatory metabolite succinate, thus inducing a metabolic switch in endogenous macrophages and microglia toward an anti-inflammatory phenotype.
Pub.: 26 Feb '18, Pinned: 22 Mar '18
Abstract: A few cases of thyroid eye disease following alemtuzumab therapy have been described in patients with multiple sclerosis. Our patient is the first case of Graves’ orbitopathy after alemtuzumab conditioning for hematopoietic stem cell transplantation.
Pub.: 12 Mar '18, Pinned: 22 Mar '18
Abstract: Multiple sclerosis is considered to be an immune mediated inflammatory disorder of the central nervous system. It mainly affects young, socioeconomic active patients. Although our armamentarium for this disease has significantly evolved in recent years some patients remain refractory to conventional therapies. In these cases, autologous hematopoietic stem cell transplantation can be considered as a therapeutic option. Decreasing morbidity, mortality, and increasing patient awareness have led to rising inquiry by our patients about this treatment option. With the aim of a standardized protocol and data registration, a Belgian working party on stem cell therapy in multiple sclerosis was established. In this paper, we report the consensus protocol of this working party on autologous hematopoietic stem cell transplantation in multiple sclerosis.
Pub.: 13 Mar '18, Pinned: 22 Mar '18
Abstract: The therapeutic efficacy of adipose-derived stem cells (ASCs) has been investigated for numerous clinical indications, including autoimmune and neurodegenerative diseases. Less is known using the crude adipose product called stromal vascular fraction (SVF) as therapy, although our previous studies demonstrated greater efficacy at late-stage disease compared to ASCs in the experimental autoimmune encephalomyelitis (EAE) mouse, a model of multiple sclerosis. In this study, SVF cells and ASCs were administered during the pathogenic progression, designated as early disease, to elucidate immunomodulatory mechanisms when high immune cell activities associated with autoimmune signaling occur. These implications are essential for clinical translation when considering timing of administration for cell therapies. We investigated the effects of SVF cells and ASCs by analyzing the spleens, peripheral blood, and central nervous system tissues throughout the course of EAE disease following administration of SVF cells, ASCs, or vehicle. In vitro, immunomodulatory potentials of SVF cells and ASCs were measured when exposed to EAE-derived splenocytes. Interestingly, treatment with SVF cells and ASCs transiently enhanced the severity of disease directly after administration, substantiating this critical immunomodulatory signaling. More importantly, it was only the EAE mice treated with SVF cells that were able to overcome the advancing pathogenesis and showed improvements by the end of the study. The frequency of lesions in spinal cords following SVF treatment correlated with diminished activities of the T helper type 1 cells, known effector cells of this disease. Co-cultures with splenocytes isolated from EAE mice revealed transcripts of interleukin-10 and transforming growth factor-β, known promoters of regulatory T cells, that were greatly expressed in SVF cells compared to ASCs, and expression levels of signaling mediators related to effector T cells were insignificant in both SVF cells and ASCs. This is the first evidence, to date, to elucidate a mechanism of action of SVF treatment in an inflammatory, autoimmune disease. Our data supports key immunomodulatory signaling between cell therapies and T cells in this T cell-mediated disease. Together, treatment with SVF mediated immunomodulatory effects that diminished effector cell activities, promoted regulatory T cells, and reduced neuroinflammation.
Pub.: 15 Mar '18, Pinned: 22 Mar '18