Cent Nerv Syst Agents Med Chem. 2010 Mar; 10(1) : 3-15
Multiple sclerosis – established and novel therapeutic approaches.

Ehling R, Berger T, Reindl M

Abstract
Multiple sclerosis (MS) is the most common disabling neurological disease in young adults characterized by recurrent relapses and / or progression that are attributable to multifocal inflammation, demyelination and axonal pathology within the central nervous system. Currently approved disease-modifying treatments achieve their effects primarily by blocking the proinflammatory response in a nonspecific manner. Their limited clinical efficacy urges a more differentiated and specific therapeutic approach. Advances in understanding the pathophysiology of MS and appreciation of the contribution of neurodegenerative processes to disease pathology have led to promising therapeutic approaches at different points along the MS disease pathway: (i) monoclonal antibody therapy has provided the opportunity to rationally direct the therapeutic intervention by specifically targeting mechanisms of the immune system such as CD52 (alemtuzumab), CD25 (daclizumab), VLA-4 (natalizumab) and CD20 (rituximab); (ii) novel oral immunomodulating agents have shown to prevent lymphocyte recirculation from lymphoid organs such as fingolimod (FTY720); (iii) blocking of intracellular signaling cascades or ion channels at the cell-surface can protect axons from degeneration and restore axonal function in experimental settings; (iv) neuroprotective agents and stem cell therapy are able to promote remyelination and axonal regeneration in vitro. Despite the tremendous efforts undertaken, a better understanding of the sequential evolution of the MS lesion and the development of clinical surrogate markers, which allow to define subsets of patients with different forms of underlying pathogenesis, is necessary. This will pave the way for an optimized treatment approach, which will likely need both to target inflammation and to focus on promotion of neuroprotection and repair.

PMID: 20236038 [PubMed – indexed for MEDLINE]

Autoimmune Dis. 2010 Dec 15;2011:164608.

Mechanisms of oxidative damage in multiple sclerosis and a cell therapy approach to treatment.

Witherick J, Wilkins A, Scolding N, Kemp K.

Multiple Sclerosis and Stem Cell Group, Institute of Clinical Neurosciences, School of Clinical Sciences, University of Bristol, Bristol BS16 1LE, UK.

Abstract
Although significant advances have recently been made in the understanding and treatment of multiple sclerosis, reduction of long-term disability remains a key goal. Evidence suggests that inflammation and oxidative stress within the central nervous system are major causes of ongoing tissue damage in the disease. Invading inflammatory cells, as well as resident central nervous system cells, release a number of reactive oxygen and nitrogen species which cause demyelination and axonal destruction, the pathological hallmarks of multiple sclerosis. Reduction in oxidative damage is an important therapeutic strategy to slow or halt disease processes. Many drugs in clinical practice or currently in trial target this mechanism. Cell-based therapies offer an alternative source of antioxidant capability. Classically thought of as being important for myelin or cell replacement in multiple sclerosis, stem cells may, however, have a more important role as providers of supporting factors or direct attenuators of the disease. In this paper we focus on the antioxidant properties of mesenchymal stem cells and discuss their potential importance as a cell-based therapy for multiple sclerosis.
PMID: 21197107 [PubMed – in process]

Curr Opin Immunol. 2010 Dec;22(6):768-74. Epub 2010 Nov 17.

Why should mesenchymal stem cells (MSCs) cure autoimmune diseases?

Uccelli A, Prockop DJ.

Department of Neurosciences Ophthalmology and Genetics, University of Genoa, Italy. auccelli@neurologia.unige.it

Abstract
The adult stem/progenitor cells from bone marrow and other tissues referred to as mesenchymal stem cells or multipotent mesenchymal stromal cells (MSCs) display a significant therapeutic plasticity as reflected by their ability to enhance tissue repair and influence the immune response both in vitro and in vivo. In this review we will focus on the paradigmatic preclinical experience achieved testing MSCs in experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis. We will emphasize how the paradigm changed over time from the original prediction that MSCs would enhance tissue repair through their transdifferentiation into somatic cells to the current paradigm that they can produce therapeutic benefits without engraftment into the injured tissues. The data will be reviewed in terms of the potentials of MSCs for therapy of autoimmune diseases.
Copyright © 2010 Elsevier Ltd. All rights reserved.
PMID: 21093239 [PubMed – in process]

Stem Cell Rev. 2010 Dec;6(4):500-6

A Consensus Statement Addressing Mesenchymal Stem Cell Transplantation for Multiple Sclerosis: It’s Time!

Siatskas C, Payne NL, Short MA, Bernard CC

Abstract
Multiple sclerosis is a neurodegenerative disease of the central nervous system that is characterized by inflammation, demyelination with associated accumulation of myelin debris, oligodendrocyte and axonal loss. Current therapeutic interventions for multiple sclerosis predominantly modulate the immune system and reduce the inflammatory insult by general, non-specific mechanisms but have little effect on the neurodegenerative component of the disease. Predictably, the overall long-term impact of treatment is limited since the neurodegenerative component of the disease, which can be the dominant process in some patients, determines permanent disability. Mesenchymal stem cells, which are endowed with potent immune regulatory and neuroprotective properties, have recently emerged as promising cellular vehicles for the treatment of MS. Preclinical evaluation in experimental models of MS have shown that MSCs are efficacious in suppressing clinical disease. Mechanisms that may underlie these effects predominantly involve the secretion of immunomodulatory and neurotrophic growth factors, which collectively act to limit CNS inflammation, stimulate neurogenesis, protect axons and promote remyelination. As a logical progression to clinical utility, the safety of these cells have been initially assessed in hematological, cardiac and inflammatory diseases. Importantly, transplantation with autologous or allogeneic MSCs has been well tolerated by patients with few significant adverse effects. On the basis of these results, new, multicentre clinical trials have been launched to assess the safety and efficacy of MSCs for inflammatory MS. It thus comes as no surprise that the coalescence of an international group of experts have convened to generate a consensus guide for the transplantation of autologous bone marrow-derived MSC which, in time, may set the foundation for the next generation of therapies for the treatment of MS patients.

Stem Cell Rev. 2010 Dec;6(4):548-59

Inflammatory cytokine induced regulation of superoxide dismutase 3 expression by human mesenchymal stem cells.

Kemp K, Gray E, Mallam E, Scolding N, Wilkins A

Abstract
Increasing evidence suggests that bone marrow derived-mesenchymal stem cells (MSCs) have neuroprotective properties and a major mechanism of action is through their capacity to secrete a diverse range of potentially neurotrophic or anti-oxidant factors. The recent discovery that MSCs secrete superoxide dismutase 3 (SOD3) may help explain studies in which MSCs have a direct anti-oxidant activity that is conducive to neuroprotection in both in vivo and in vitro. SOD3 attenuates tissue damage and reduces inflammation and may confer neuroprotective effects against nitric oxide-mediated stress to cerebellar neurons; but, its role in relation to central nervous system inflammation and neurodegeneration has not been extensively investigated. Here we have performed a series of experiments showing that SOD3 secretion by human bone marrow-derived MSCs is regulated synergistically by the inflammatory cytokines TNF-alpha and IFN-gamma, rather than through direct exposure to reactive oxygen species. Furthermore, we have shown SOD3 secretion by MSCs is increased by activated microglial cells. We have also shown that MSCs and recombinant SOD are able to increase both neuronal and axonal survival in vitro against nitric oxide or microglial induced damage, with an increased MSC-induced neuroprotective effect evident in the presence of inflammatory cytokines TNF-alpha and IFN-gamma. We have shown MSCs are able to convey these neuroprotective effects through secretion of soluble factors alone and furthermore demonstrated that SOD3 secretion by MSCs is, at least, partially responsible for this phenomenon. SOD3 secretion by MSCs maybe of relevance to treatment strategies for inflammatory disease of the central nervous system.
PMID: 20683679 [PubMed – in process]

Stem Cell Rev. 2010 Dec;6(4):500-6.

A consensus statement addressing mesenchymal stem cell transplantation for multiple sclerosis: it’s time!

Siatskas C, Payne NL, Short MA, Bernard CC.

Monash immunology and stem cell laboratories, Monash University, Clayton, Victoria, 3800, Australia. christopher.siatskas@monash.edu

Abstract
Multiple sclerosis is a neurodegenerative disease of the central nervous system that is characterized by inflammation, demyelination with associated accumulation of myelin debris, oligodendrocyte and axonal loss. Current therapeutic interventions for multiple sclerosis predominantly modulate the immune system and reduce the inflammatory insult by general, non-specific mechanisms but have little effect on the neurodegenerative component of the disease. Predictably, the overall long-term impact of treatment is limited since the neurodegenerative component of the disease, which can be the dominant process in some patients, determines permanent disability. Mesenchymal stem cells, which are endowed with potent immune regulatory and neuroprotective properties, have recently emerged as promising cellular vehicles for the treatment of MS. Preclinical evaluation in experimental models of MS have shown that MSCs are efficacious in suppressing clinical disease. Mechanisms that may underlie these effects predominantly involve the secretion of immunomodulatory and neurotrophic growth factors, which collectively act to limit CNS inflammation, stimulate neurogenesis, protect axons and promote remyelination. As a logical progression to clinical utility, the safety of these cells have been initially assessed in hematological, cardiac and inflammatory diseases. Importantly, transplantation with autologous or allogeneic MSCs has been well tolerated by patients with few significant adverse effects. On the basis of these results, new, multicentre clinical trials have been launched to assess the safety and efficacy of MSCs for inflammatory MS. It thus comes as no surprise that the coalescence of an international group of experts have convened to generate a consensus guide for the transplantation of autologous bone marrow-derived MSC which, in time, may set the foundation for the next generation of therapies for the treatment of MS patients.
PMID: 20665128 [PubMed – indexed for MEDLINE]

Expert Rev Neurother. 2001 Nov;1(2):267-73.

Stem cells as therapeutics for neurodegenerative disorders?

Mattson MP.

Laboratory of Neurosciences, National Institute on Aging GRC 4F01, 5600 Nathan Shock Drive, Baltimore, MD 21224, USA. mattsonm@grc.nia.nih.gov

Abstract
Aging is associated with a progressive increase in the risk of several prominent neurodegenerative disorders, including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, stroke and amyotrophic lateral sclerosis. In each of these disorders specific populations of neurons become dysfunctional, then die and are not replaced. The adult brain and spinal cord contain populations of so-called neural stem cells (self-renewing and multipotent) and neural precursor cells (specified to a certain fate, but still mitotic) that may provide a continuing source of new neurons and glial cells during successful aging and after injury to the nervous system. Recent studies have shown that stem cells from embryos and adults can be transplanted into the nervous system, differentiate into neurons and glia and restore lost function in experimental models of neurodegenerative diseases. Embryonic stem cells may be a particularly effective donor cell type for transplantation-based therapies. Efficacy of stem cell therapies remains to be established in clinical trials in humans. Another approach is to mobilize endogenous neural stem cells. Animals studies have shown that dietary and behavioral modifications can indeed stimulate neurogenesis. Molecular and cellular mechanisms that regulate the proliferation, differentiation and survival of neural stem cells and neural precursor cells are being elucidated and are revealing novel targets for the development of pharmaceuticals that promote neurogenesis.
PMID: 19811037 [PubMed]

Curr Stem Cell Res Ther. 2010 Oct 18. [Epub ahead of print]

Mesenchymal Stem Cells for Multiple Sclerosis: Does Neural Differentiation Really Matter?

Uccelli A, Morando S, Bonanno S, Bonanni I, Leonardi A, Mancardi G.

Department of Neurosciences, Ophthalmology and Genetics, University of Genoa, Genoa. auccelli@neurologia.unige.it.

Abstract
The lack of therapies fostering remyelination and regeneration of the neural network deranged by the autoimmune attack occurring in multiple sclerosis (MS), is raising great expectations about stem cells therapies for tissue repair. Mesenchymal stem cells (MSCs) have been proposed as a possible treatment for MS due to the reported capacity of transdifferentiation into neural cells and their ability at modulating immune responses. However, recent studies have demonstrated that many other functional properties are likely to play a role in the therapeutic plasticity of MSCs, including anti-apoptotic, trophic and anti-oxidant effects. These features are mostly based on the paracrine release of soluble molecules, often dictated by local environmental cues. Based on the modest evidence of long-term engraftment and the striking clinical effects that are observed immediately after MSCs administration in the experimental model of MS, we do not favor a major role for transdifferentiation as an important mechanism involved in the therapeutic effect of MSCs.
PMID: 20955153 [PubMed – as supplied by publisher]

J Neuroimmunol. 2010 Oct 8;227(1-2):185-9. Epub 2010 Aug 21.

Bone marrow mesenchymal stem cell transplantation in patients with multiple sclerosis: a pilot study.

Yamout B, Hourani R, Salti H, Barada W, El-Hajj T, Al-Kutoubi A, Herlopian A, Baz EK, Mahfouz R, Khalil-Hamdan R, Kreidieh NM, El-Sabban M, Bazarbachi A.

Departments of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon. yamoutba@idm.net.lb

Abstract
We explore the safety, and therapeutic benefit of intrathecal injection of ex-vivo expanded autologous bone marrow derived mesenchymal stem cells (BM-MSCs) in 10 patients with advanced multiple sclerosis (MS). Patients were assessed at 3, 6 and 12 months. Assessment at 3-6 months revealed Expanded Disability Scale Score (EDSS) improvement in 5/7, stabilization in 1/7, and worsening in 1/7 patients. MRI at 3 months revealed new or enlarging lesions in 5/7 and Gadolinium (Gd+) enhancing lesions in 3/7 patients. Vision and low contrast sensitivity testing at 3 months showed improvement in 5/6 and worsening in 1/6 patients. Early results show hints of clinical but not radiological efficacy and evidence of safety with no serious adverse events.
Copyright © 2010 Elsevier B.V. All rights reserved.
PMID: 20728948 [PubMed – indexed for MEDLINE]

Ann Hematol. 2010 Sep 25;

Clinical outcome of autologous peripheral blood stem cell transplantation in opticospinal and conventional forms of secondary progressive multiple sclerosis in a
Chinese population.

Xu J, Ji BX, Su L, Dong HQ, Sun WL, Wan SG, Liu YO, Zhang P, Liu CY

Abstract
To evaluate clinical outcomes of autologous peripheral blood stem cell transplantation (APBCST) between opticospinal multiple sclerosis (OSMS) and conventional multiple sclerosis (CMS) during disease progressive stage in a Chinese population. Thirty-six secondary progressive MS patients, among whom 21 were with OSMS and 15 with CMS, underwent APBSCT and were followed up for an average of 48.92 months (range, 10-91 months). Peripheral blood stem cells were obtained by leukapheresis after mobilization with granulocyte colony-stimulating factor. Modified BEAM conditioning regimen (Tiniposide, melphalan, carmustin, and cytosine arabinoside) were administered. Outcomes were evaluated using the expanded disability status scale (EDSS). No maintenance treatment was administered if there was no disease progression. No treatment-related mortality occurred. Among the 36 patients, one OSMS patient dropped during the follow-up. Among the 22 relapse-free patients, 20 were with continuous neurological improvement without any relapse events, and two remained in neurologically stable states. Among the 13 relapse patients, seven had experienced of neurological relapse, but with no progression during the follow-up period; and six experienced neurological deterioration after transplantation and needed further immunosuppressant treatment. The confirmed relapse-free survival rate was 62.9% and progression-free survival rate was 83.3% after 91 months according to Kaplan and Meier survival curves. Eleven of the 20 OSMS patients (55%) and two of the 15 CMS patients (13.3%) stayed in disease active group (P = 0.014). For the 20 OSMS patients, the overall EDSS score decreased significantly after transplantation (P = 0.016), while visual functions had no significant improvement (P = 0.716). Progressive OSMS has a higher relapse rate than CMS following APBSCT.
PMID: 20872003 [PubMed – as supplied by publisher]

Cell Transplant. 2010 Sep 30. doi: 10.3727/096368910X532855. [Epub ahead of print]

The treatment of neurodegenerative disorders using umbilical cord blood and menstrual blood-derived stem cells.

Sanberg PR, Eve DJ, Willing AE, Garbuzova-Davis S, Tan J, Sanberg CD, Allickson JG, Cruz LE, Borlongan CV.

Center Of Excellence for Aging and Brain Repair, Dept. Neurosurgery and Brain Reapir, University of South Florida, Tampa FL, psanberg@health.usf.edu.

Abstract
Stem Cell transplantation is a potentially important means of treatment for a number of disorders. Two different stem cell populations of interest are mononuclear umbilical cord blood cells and menstrual blood-derived stem cells. These cells are relatively easy to obtain, appear to be pluripotent and are immunologically immature. These cells, particularly umbilical cord blood cells, have been studied as either single or multiple injections in a number of animal models of neurodegenerative disorders with some degree of success, including stroke, Alzheimer’s disease, amyotrophic lateral sclerosis, and Sanfilippo syndrome type B. Evidence of anti-inflammatory effects and secretion of specific cytokines and growth factors that promote cell survival, rather than cell replacement have been detected in both transplanted cells.
PMID: 20887684 [PubMed – as supplied by publisher]

Bone Marrow Transplant. 2010 Aug 9;

Hematopoietic SCT for the treatment of multiple sclerosis.

Atkins H

Abstract
Multiple sclerosis (MS) is the leading autoimmune indication for autologous hematopoietic SCT (aHSCT). Patient selection criteria and transplant interventions have been refined through a series of cohort and registry studies. High- and low-intensity chemotherapy-based conditioning regimens have been used, creating trade-offs between toxicity and effectiveness. TBI has been associated with greater toxicity and poor outcomes. aHSCT stops MS relapses and lessens the disability in malignant MS, which otherwise rapidly incapacitates patients. Better responses occur in progressive MS earlier in the disease when it has a more inflammatory nature. aHSCT prevents further disability in many patients, but some actually recover from their infirmities. Current regimens and supportive care result in very low morbidity and mortality. MS patients experience unique complications in addition to the expected toxicities. Cytokines used alone for stem-cell mobilization may induce MS flares but are safe to be used in combination with steroids or cytotoxic agents. Urinary tract infections, herpes virus reactivation and an engraftment syndrome may occur early after aHSCT. Rarely secondary autoimmune diseases have been reported late after HSCT. Increasing experience in caring for patients with MS has reduced the frequency and severity of toxicity. Conceived as an opportunity to ‘reboot’ a tolerant immune system, aHSCT is successful in treating patients with MS that is refractory to conventional immunomodulatory drugs.Bone Marrow Transplantation advance online publication, 9 August 2010; doi:10.1038/bmt.2010.168.
PMID: 20697363 [PubMed – as supplied by publisher]

Adv Exp Med Biol. 2010;671:41-57

Stem cell transplantation methods.

Tran KD, Ho A, Jandial R

Abstract
Just a few short years ago, we still used to think that we were born with a finite number of irreplaceable neurons. However, in recent years, there has been increasingly persuasive evidence that suggests that neural stem cell (NSC) maintenance and differentiation continue to take ace throughout the mammal’s lifetime. Studies suggest that neural stem cells not only persist to mammalian adulthood, but also play a continuous role in brain tissue repair throughout the organism’s lifespan. These preliminary results further imply that NSC transplantation strategies might have therapeutic promise in treating neurodegenerative diseases often characterized by isolated or global neuronal and glialloss. The destruction of neural circuitry in neuropathologies such as stroke, Parkinson’s disease, MS, SCI prevents signals from being sent throughout the body effectively and is devastating and necessitates a cure. NSC transplantation is among one of the foremost researched fields because it offers promising therapeutic value for regenerative therapy central nervous system (CNS) diseases. Both chemotropic and exogenous cell graft mechanisms ofCNS repair are under review for their therapeutic value and it is hoped that one day, these findings will be applied to human neurodegenerative disorders. The potential applications for NSC transplantations to treat both isolated and global neurodysfunction in humans are innumerable; these prospects include inherited pediatric neurodegenerative and metabolic disorders such as lysosomal storage diseases including leukodystrophies, Sandhoff disease, hypoxic-ischemic encephalopathy and adult CNS disorders characterized by neuronal or glial cell loss such as Parkinson’s disease, multiple sclerosis, stroke and spinal cord injury.
PMID: 20455494 [PubMed – indexed for MEDLINE]

Mult Scler. 2010 Aug;16(8):909-18

Characterization of in vitro expanded bone marrow-derived mesenchymal stem cells from patients with multiple sclerosis.

Mallam E, Kemp K, Wilkins A, Rice C, Scolding N

Abstract
Recent studies have investigated the potential of autologous bone marrow-derived mesenchymal stem cells (MSCs) as a therapy for multiple sclerosis. Whether MSCs from individuals with multiple sclerosis are functionally and/or phenotypically abnormal has received less attention. Through our Phase I clinical trial, SIAMMS, we were able to isolate and characterize MSCs from individuals with multiple sclerosis. The objective of the study was to demonstrate that MSCs from individuals with multiple sclerosis show no significant differences from MSCs derived from individuals without multiple sclerosis. MSCs were isolated from bone marrow aspirates from four SIAMMS participants. We were also able to isolate MSCs from bone marrow obtained during a total hip replacement operation on an individual with multiple sclerosis. Control MSCs were isolated from bone marrow acquired during total hip replacement operations on five individuals without MS. MSCs were characterized using standard criteria: plastic adherence, differentiation along adipogenic/osteogenic/chondrogenic lineages, and expression of specific cell surface antigens. We also determined their proliferation potential. MSCs from individuals with multiple sclerosis and individuals without multiple sclerosis were similar in proliferation, differentiation potential and cell surface antigen expression. This has relevance to scientific studies investigating the therapeutic potential of autologous MSCs which primarily utilize MSCs from individuals without multiple sclerosis, and relevance to clinical studies extrapolating from these scientific findings.
PMID: 20542920 [PubMed – in process]

J Neuroimmunol. 2010 Jul 27;224(1-2):101-7

Cell replacement therapies to promote remyelination in a viral model of demyelination.

Tirotta E, Carbajal KS, Schaumburg CS, Whitman L, Lane TE

Abstract
Persistent infection of the central nervous system (CNS) of mice with the neuroadapted JHM strain of mouse hepatitis (MHV) is characterized by ongoing demyelination mediated by inflammatory T cells and macrophages that is similar both clinically and histologically with the human demyelinating disease multiple sclerosis (MS). Although extensive demyelination occurs in mice persistently infected with MHV there is only limited remyelination. Therefore, the MHV model of demyelination is a relevant model for studying disease and evaluating therapeutic approaches to protect cells of the oligodendrocyte lineage and promote remyelination. This concept is further highlighted as the etiology of MS remains enigmatic, but viruses have long been considered as potential triggering agents in initiating and/or maintaining MS symptoms. As such, understanding mechanisms associated with promoting repair within the CNS in the context of a persistent viral infection is critical given the possible viral etiology of MS. This review focuses on recent studies using either mouse neural stem cells (NSCs) or human oligodendrocyte progenitor cells (OPCs) derived from human embryonic stem cell (hESC) to promote remyelination in mice persistently infected with MHV. In addition, the potential role for chemokines in positional migration of transplanted cells is addressed.
PMID: 20627412 [PubMed – indexed for MEDLINE]

Curr Opin Neurol. 2010 Jun;23(3):218-25

Stem cell transplantation in multiple sclerosis.

Uccelli A, Mancardi G

Abstract
The recent advances in our understanding of stem cell biology, the availability of innovative techniques that allow large-scale acquisition of stem cells, and the increasing pressure from the multiple sclerosis (MS) patient community seeking tissue repair strategies have launched stem cell treatments as one of the most exciting and difficult challenges in the MS field. Here, we provide an overview of the current status of stem cell research in MS focusing on secured actuality, reasonable hopes and unrealistic myths. RECENT FINDINGS: Results obtained from small clinical studies with transplantation of autologous hematopoietic stem cells have demonstrated that this procedure is feasible and possibly effective in severe forms of MS but tackles exclusively inflammation without affecting tissue regeneration. Results from preclinical studies with other adult stem cells such as mesenchymal stem cells and neural precursor cells have shown that they may be a powerful tool to regulate pathogenic immune response and foster tissue repair through bystander mechanisms with limited cell replacement. However, the clinical translation of these results still requires careful evaluation. CONCLUSION: Current experimental evidence suggests that the sound clinical exploitation of stem cells for MS may lead to novel strategies aimed at blocking uncontrolled inflammation, protecting neurons and promoting remyelination but not at restoring the chronically deranged neural network responsible for irreversible disability typical of the late phase of MS.
PMID: 20375893 [PubMed – indexed for MEDLINE]

Mult Scler. 2010 Jun;16(6):685-93

High-dose immunoablation with autologous haematopoietic stem cell transplantation in aggressive multiple sclerosis: a single centre 10-year experience.

Krasulová E, Trneny M, Kozák T, Vacková B, Pohlreich D, Kemlink D, Kobylka P, Kovárová I, Lhotáková P, Havrdová E

Abstract
There are multiple sclerosis patients who suffer from an aggressive course of the disease with severe relapses and rapid accumulation of disability despite adequate treatment. In such cases high-dose immunoablation with autologous haematopoietic stem cell transplantation (ASCT) may be considered. Our objective was to report our experience with 26 multiple sclerosis patients treated with ASCT within the years 1998-2008. Twenty-six patients (Expanded Disability Status Scale 2.5-7.5 (median 6.0), multiple sclerosis duration 2-19 years (median 7)) with aggressive multiple sclerosis underwent autologous haematopoietic stem cell transplantation. Stem cells were mobilized by high-dose cyclophosphamide and granulocyte colony-stimulating factor, BEAM (carmustine, etoposide, cytarabine, melphalan) was used for immunoablation. Patients were evaluated at baseline and every six months post ASCT for adverse events and clinical outcome. Follow-up period was 11-132 months (median 66). Progression-free survival was calculated using the Kaplan- Meier method. At 3 and 6 years of follow-up 70.8% and 29.2% of patients respectively were free of progression. Patients with relapsing multiple sclerosis course, disease duration PMID: 20350962 [PubMed – indexed for MEDLINE]

Cent Nerv Syst Agents Med Chem. 2010 Mar;10(1):3-15

Multiple sclerosis – established and novel therapeutic approaches.

Ehling R, Berger T, Reindl M

Abstract
Multiple sclerosis (MS) is the most common disabling neurological disease in young adults characterized by recurrent relapses and / or progression that are attributable to multifocal inflammation, demyelination and axonal pathology within the central nervous system. Currently approved disease-modifying treatments achieve their effects primarily by blocking the proinflammatory response in a nonspecific manner. Their limited clinical efficacy urges a more differentiated and specific therapeutic approach. Advances in understanding the pathophysiology of MS and appreciation of the contribution of neurodegenerative processes to disease pathology have led to promising therapeutic approaches at different points along the MS disease pathway: (i) monoclonal antibody therapy has provided the opportunity to rationally direct the therapeutic intervention by specifically targeting mechanisms of the immune system such as CD52 (alemtuzumab), CD25 (daclizumab), VLA-4 (natalizumab) and CD20 (rituximab); (ii) novel oral immunomodulating agents have shown to prevent lymphocyte recirculation from lymphoid organs such as fingolimod (FTY720); (iii) blocking of intracellular signaling cascades or ion channels at the cell-surface can protect axons from degeneration and restore axonal function in experimental settings; (iv) neuroprotective agents and stem cell therapy are able to promote remyelination and axonal regeneration in vitro. Despite the tremendous efforts undertaken, a better understanding of the sequential evolution of the MS lesion and the development of clinical surrogate markers, which allow to define subsets of patients with different forms of underlying pathogenesis, is necessary. This will pave the way for an optimized treatment approach, which will likely need both to target inflammation and to focus on promotion of neuroprotection and repair.
PMID: 20236038 [PubMed – indexed for MEDLINE]

Nat Rev Neurol. 2010 May;6(5):247-55. Epub 2010 Apr 20.

Stem cell transplantation in multiple sclerosis: current status and future prospects.

Martino G, Franklin RJ, Van Evercooren AB, Kerr DA; Stem Cells in Multiple Sclerosis (STEMS) Consensus Group.

Institute of Experimental Neurology-DIBIT 2, Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy. martino.gianvito@hsr.it

Abstract
This article provides an overview of the current knowledge relating to the potential use of transplanted stem cells in the treatment of patients with multiple sclerosis (MS). Two types of stem cells, CNS-derived neural stem/precursor cells (NPCs) and bone marrow-derived mesenchymal stem cells (MSCs) are considered to provide reproducible and robust therapeutic effects when intravenously or intrathecally injected into both rodents and primates with experimental autoimmune encephalomyelitis. Furthermore, preliminary safety data concerning the use of intrathecally injected autologous MSCs in patients with progressive MS are available. We discuss how the data gathered to date challenge the narrow view that the therapeutic effects of NPCs and MSCs observed in the treatment of MS are accomplished solely by cell replacement. Both types of stem cell, when transplanted systemically, might instead influence disease outcome by releasing a plethora of factors that are immunomodulatory or neuroprotective, thereby directly or indirectly influencing the regenerative properties of intrinsic CNS stem/precursor cells.
PMID: 20404843 [PubMed – indexed for MEDLINE]

Expert Rev Clin Immunol. 2010 May;6(3):347-52

Hematopoietic stem cell transplantation in multiple sclerosis: a review of the clinical experience and a report of an international meeting.

Karussis D, Vaknin-Dembinsky A

Abstract
Hematopoietic stem cell transplantation (HSCT), both allogeneic and autologous, has become one of the hottest topics in clinical immunology. One of the main autoimmune diseases in which HSCT has been extensively tried during the last decade is multiple sclerosis (MS). A few original papers and many anecdotal reports have indicated a beneficial effect of this treatment in MS, leading to stabilization or improvement in a large proportion of the treated patients. However, although hundreds of MS patients have been treated with HSCT, different conditioning and treatment protocols have been used in each center, making it difficult to organize and summarize the results from all of these small studies. Moreover, there is currently no completed controlled study with HSCT in MS. In this review, the cumulative experiences from several centers and countries in the world are summarized, based on the data presented at a recent international meeting in Moscow, Russia, entitled ‘Stem Cell Transplantation in Multiple Sclerosis: Sharing the Experience’.
PMID: 20441420 [PubMed – indexed for MEDLINE]

Nat Rev Neurol. 2010 May;6(5):247-55

Stem cell transplantation in multiple sclerosis: current status and future prospects.

Martino G, Franklin RJ, Van Evercooren AB, Kerr DA,

Abstract
This article provides an overview of the current knowledge relating to the potential use of transplanted stem cells in the treatment of patients with multiple sclerosis (MS). Two types of stem cells, CNS-derived neural stem/precursor cells (NPCs) and bone marrow-derived mesenchymal stem cells (MSCs) are considered to provide reproducible and robust therapeutic effects when intravenously or intrathecally injected into both rodents and primates with experimental autoimmune encephalomyelitis. Furthermore, preliminary safety data concerning the use of intrathecally injected autologous MSCs in patients with progressive MS are available. We discuss how the data gathered to date challenge the narrow view that the therapeutic effects of NPCs and MSCs observed in the treatment of MS are accomplished solely by cell replacement. Both types of stem cell, when transplanted systemically, might instead influence disease outcome by releasing a plethora of factors that are immunomodulatory or neuroprotective, thereby directly or indirectly influencing the regenerative properties of intrinsic CNS stem/precursor cells.
PMID: 20404843 [PubMed – indexed for MEDLINE]

Mult Scler. 2010 Apr;16(4):503-10

The therapeutic potential of mesenchymal stem cell transplantation as a treatment for multiple sclerosis: consensus report of the
International MSCT Study Group.

Freedman MS, Bar-Or A, Atkins HL, Karussis D, Frassoni F, Lazarus H, Scolding N, Slavin S, Le Blanc K, Uccelli A,

Abstract
Current therapies for multiple sclerosis effectively reduce inflammation, but do little in terms of repair to the damaged central nervous system. Cell-based therapies may provide a new strategy for bolstering regeneration and repair through neuro-axonal protection or remyelination. Mesenchymal stem cells modulate pathological responses in experimental autoimmune encephalitis, alleviating disease, but also stimulate repair of the central nervous system through the release of soluble factors. Autologous and allogeneic mesenchymal stem cells have been safely administered to individuals with hemato-oncological diseases and in a limited number of patients with multiple sclerosis. It is therefore reasonable to move mesenchymal stem cells transplantation into properly controlled human studies to explore their potential as a treatment for multiple sclerosis. Since it is likely that the first such studies will probably involve only small numbers of patients in a few centers, we formed an international panel comprising multiple sclerosis neurology and stem cell experts, as well as immunologists. The aims were to derive a consensus on the utilization of mesenchymal stem cells for the treatment of multiple sclerosis, along with protocols for the culture of the cells and the treatment of patients. This article reviews the consensus derived from our group on the rationale for mesenchymal stem cell transplantation, the methodology for generating mesenchymal stem cells and the first treatment protocol for multiple sclerosis patients.
PMID: 20086020 [PubMed – indexed for MEDLINE]

Cell Adh Migr. 2010 Apr-Jun;4(2):235-40

Adult human mesenchymal cells proliferate and migrate in response to chemokines expressed in demyelination.

Rice CM, Scolding NJ

Abstract
Systemic delivery of multipotent mesenchymal stem cells (MSC) may be of benefit in the treatment of neurological diseases, including multiple sclerosis (MS). Certainly, animal studies have demonstrated functional benefits following MSC transplantation, although the mechanisms by which MSCs migrate to lesions and stimulate repair remain unknown. Chemokines stimulate migration in other settings. In this study, we systematically explore the migratory and proliferative responses of human MSCs (hMSC) to chemokines expressed in MS lesions. We demonstrate that these chemokines trigger hMSC migration. In addition, we show that RANTES and IP-10 promote hMSC proliferation.
PMID: 20234187 [PubMed – in process]

Discov Med. 2010 Mar;9(46):236-42

The potential of mesenchymal stem cells for neural repair.

Miller RH, Bai L, Lennon DP, Caplan AI

Abstract
Developing effective therapies for serious neurological insults remains a major challenge for biomedical research. Despite intense efforts, the ability to promote functional recovery after contusion injuries, ischemic insults, or the onset of neurodegenerative diseases in the brain and spinal cord remains very limited even while the need for such therapies is increasing with an aging population. Recent studies suggest that cellular therapies utilizing mesenchymal stem cells (MSCs) may provide a functional benefit in a wide range of neurological insults. MSCs derived from a variety of tissue sources have been therapeutically evaluated in animal models of stroke, spinal cord injury, and multiple sclerosis. In each situation, treatment with MSCs results in substantial functional benefit and these pre-clinical studies have led to the initiation of a number of clinical trials worldwide in neural repair.
PMID: 20350491 [PubMed – indexed for MEDLINE]

Discov Med. 2010 Mar;9(46):236-42.

The potential of mesenchymal stem cells for neural repair.

Miller RH, Bai L, Lennon DP, Caplan AI.

Centers for Stem Cells and Regenerative Medicine, Translational Neuroscience, Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA. rhm3@case.edu

Abstract
Developing effective therapies for serious neurological insults remains a major challenge for biomedical research. Despite intense efforts, the ability to promote functional recovery after contusion injuries, ischemic insults, or the onset of neurodegenerative diseases in the brain and spinal cord remains very limited even while the need for such therapies is increasing with an aging population. Recent studies suggest that cellular therapies utilizing mesenchymal stem cells (MSCs) may provide a functional benefit in a wide range of neurological insults. MSCs derived from a variety of tissue sources have been therapeutically evaluated in animal models of stroke, spinal cord injury, and multiple sclerosis. In each situation, treatment with MSCs results in substantial functional benefit and these pre-clinical studies have led to the initiation of a number of clinical trials worldwide in neural repair.
PMID: 20350491 [PubMed – indexed for MEDLINE]

Bone Marrow Transplant. 2010 Feb;45(2):239-48

Brazilian experience with two conditioning regimens in patients with multiple sclerosis: BEAM/horse ATG and CY/rabbit ATG.

Hamerschlak N, Rodrigues M, Moraes DA, Oliveira MC, Stracieri AB, Pieroni F, Barros GM, Madeira MI, Simões BP, Barreira AA, Brum DG, Ribeiro AA, Kutner JM, Tylberi CP, Porto PP, Santana CL, Neto JZ, Barros JC, Paes AT, Burt RK, Oliveira EA, Mastropietro AP, Santos AC, Voltarelli JC

Abstract
Studies have shown that autologous hematopoietic SCT (HSCT) can be used as an intensive immunosuppressive therapy to treat refractory patients and to prevent the progression of multiple sclerosis (MS). This is a prospective multicentric Brazilian MS trial comparing two conditioning regimens: BEAM/horse ATG and CY/rabbit ATG. Most (80.4%) of the 41 subjects in the study had the secondary progressive MS subtype and the mean age was 42 years. The baseline EDSS score in 58.5% of the subjects was 6.5 and 78% had a score of 6.0 or higher, respectively. The complication rate during the intra-transplantation period was 56% for all patients: 71.4% of the patients in the BEAM/hATG group and 40% in the CY/rATG group (P=0.04). Three subjects (7.5%) died of cardiac toxicity, sepsis and alveolar hemorrhage, all of them in the BEAM/ATG group. EFS was 58.54% for all patients: 47% in the BEAM/hATG group and 70% in the CY/rATG group (P=0.288). In conclusion, the CY/rATG regimen seems to be associated with similar outcome results, but presented less toxicity when compared with the BEAM/hATG regimen. Long-term follow-up would be required to fully assess the differences in therapeutic effectiveness between the two regimens.
PMID: 19584827 [PubMed – indexed for MEDLINE]

Expert Rev Clin Immunol. 2010 Jan;6(1):77-88

Update on the treatment options for multiple sclerosis.

Niino M, Sasaki H

Abstract
Recent progress in the treatment of multiple sclerosis (MS) is remarkable, and the introduction of new therapies is yielding improvements in the management of MS. Furthermore, clinical trials with many different types of agents, especially selected monoclonal antibodies, have been undertaken or are ongoing, and some of the agents involved will probably be available as treatments for MS in the near future. Although these new and promising agents include targeted immunotherapies, some of them have limitations such as associated severe adverse events and the development of neutralizing antibodies. With regard to risk-benefit ratios, pharmacogenetics could shed light on inherited differences in drug metabolism and response, which would make individualized therapy possible in MS. Here, we review the recent progress in current therapeutic strategies for MS, and the potential options for future MS treatment.
PMID: 20383893 [PubMed – indexed for MEDLINE]

Results Probl Cell Differ. 2010;51:237-57

Immuno-therapeutic potential of haematopoietic and mesenchymal stem cell transplantation in MS.

Muraro PA, Uccelli A

Abstract
In the last few years there has been extraordinary progress in the field of stem cell research. Two types of stem cells populate the bone marrow: haematopoietic stem/progenitor cells (HSC) and mesenchymal stem cells (MSC). The capacity of HSC to repopulate the blood has been known and exploited therapeutically for at least four decades. Today, haematopoietic stem cell transplantation (HSCT) holds a firm place in the therapy of some haematological malignancies, and a potential role of HSCT for treatment of severe autoimmune diseases has been explored in small-scale clinical studies. Multiple sclerosis (MS) is the noncancerous immune mediated disease for which the greatest number of transplants has been performed to date. The results of clinical studies are double-faced: on the one hand, HSCT has demonstrated powerful effects on acute inflammation, arresting the development of focal CNS lesions and clinical relapses; on the other hand, the treatment did not arrest chronic worsening of disability in most patients with secondary progressive MS, suggesting limited or no beneficial effects on the chronic processes causing progressive disability. MSC are a more recent addition to the range of experimental therapies being developed to treat MS. While interest in MSC usage was originally raised by their potential capacity to differentiate into different cell lineages, recent work showing their interesting immunological properties has led to a revised concept, envisioning their utilization for immuno-modulatory purposes. In this review we will summarize the current clinical and experimental evidence on HSC and MSC and outline some key questions warranting further investigation in this exciting research area.
PMID: 19513637 [PubMed – in process]

Expert Opin Biol Ther. 2009 Dec;9(12):1487-97

Bone-marrow-derived mesenchymal stem cell therapy for neurodegenerative diseases.

Sadan O, Melamed E, Offen D

Abstract
BACKGROUND: Stem-cell-based therapy is a promising new approach to handling neurodegenerative diseases. One of the most promising cellular sources is bone-marrow-derived mesenchymal stem cells (MSCs) also termed multipotent stromal cells. MSCs represent an autologous source and are abundant and non-tumorigenic. Additionally, MSCs possess the useful characteristics of homing and chemokine secretion. OBJECTIVE/METHODS: Since neurodegenerative diseases have many pathological processes in common, a specific therapeutic agent could potentially ameliorate the symptoms of several distinct neurodegenerative diseases. In this review we demonstrate the wide variety of mechanisms by which MSCs can influence neurodegenerative processes. RESULTS/CONCLUSIONS: The mechanisms by which transplanted MSCs influence neurodegenerative diseases can be broadly classified as cellular replacement or paracrine secretion, with the latter subdivided into trophic factor secretion or immunomodulation by cytokines. Emerging research suggests that genetic manipulations before transplantation could enhance the therapeutic potential of MSCs. Such manipulation could turn the cells into a ‘Trojan horse’, to deliver specific proteins, or promote reprogramming of the MSCs into the neural lineage. Clinical trials testing MSC-based therapies for familial amyotrophic lateral sclerosis and multiple sclerosis are in progress.
PMID: 19821796 [PubMed – indexed for MEDLINE]

ILAR J. 2009;51(1):24-41

Preclinical assessment of stem cell therapies for neurological diseases.

Joers VL, Emborg ME

Abstract
Stem cells, as subjects of study for use in treating neurological diseases, are envisioned as a replacement for lost neurons and glia, a means of trophic support, a therapeutic vehicle, and, more recently, a tool for in vitro modeling to understand disease and to screen and personalize treatments. In this review we analyze the requirements of stem cell-based therapy for clinical translation, advances in stem cell research toward clinical application for neurological disorders, and different animal models used for analysis of these potential therapies. We focus on Parkinson’s disease (typically defined by the progressive loss of dopaminergic nigral neurons), stroke (neurodegeneration associated with decreased blood perfusion in the brain), and multiple sclerosis (an autoimmune disorder that generates demyelination, axonal damage, astrocytic scarring, and neurodegeneration in the brain and spinal cord). We chose these disorders for their diversity and the number of people affected by them. An additional important consideration was the availability of multiple animal models in which to test stem cell applications for these diseases. We also discuss the relationship between the limited number of systematic stem cell studies performed in animals, in particular nonhuman primates and the delayed progress in advancing stem cell therapies to clinical success.
PMID: 20075496 [PubMed – indexed for MEDLINE]

Curr Mol Med. 2009 Nov;9(8):992-1016

Stem cell and gene therapeutic strategies for the treatment of multiple sclerosis.

Siatskas C, Bernard CC

Abstract
Multiple sclerosis is a disease of the central nervous system that predmoninantly affects young adults. The pathogenic mechanisms are complex, however numerous studies indicate that the disease is initiated by an autoimmune attack on protein targets present in the central nervous system. Given that a dysfunctional immune system perpetuates the pathophysiological mechanisms that characterize this inflammatory disorder, several therapeutic approaches that target immune cells or their secreted mediators have been generated and are currently used clinically. Although these strategies have been partially beneficial to a proportion of patients, current therapies are not particularly effective at preventing disease progression. As such there is a large and unmet need for the development of more effective treatments. Owing to a number of promising results obtained in mouse models of multiple sclerosis, cell therapies implementing hematopoietic, mesenchymal and neural stem cells may provide practical vehicles for in situ immunomodulation, neuroprotection and regeneration. In concert with these approaches, gene therapy strategies are being investigated to restore antigen-specific tolerance or to deliver anti-inflammatory molecules. Furthermore targeted delivery of glial or neurotropic factors, which counteract the activity of inhibitory molecules within the neurodegenerative component of the lesion, is also being pursued. It is conceivable that these experimental approaches alone, or in combination with emerging and current treatments, may establish a rational protocol for the treatment of multiple sclerosis and potentially other autoimmune disorders.
PMID: 19747118 [PubMed – indexed for MEDLINE]

Stem Cells. 2009 Oct;27(10):2624-35.

Adipose-derived mesenchymal stem cells ameliorate chronic experimental autoimmune encephalomyelitis.

Constantin G, Marconi S, Rossi B, Angiari S, Calderan L, Anghileri E, Gini B, Bach SD, Martinello M, Bifari F, Galiè M, Turano E, Budui S, Sbarbati A, Krampera M, Bonetti B.

Department of Pathology, University of Verona, Italy. gabriela.constantin@univr.it

Abstract
Mesenchymal stem cells (MSCs) represent a promising therapeutic approach for neurological autoimmune diseases; previous studies have shown that treatment with bone marrow-derived MSCs induces immune modulation and reduces disease severity in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. Here we show that intravenous administration of adipose-derived MSCs (ASCs) before disease onset significantly reduces the severity of EAE by immune modulation and decreases spinal cord inflammation and demyelination. ASCs preferentially home into lymphoid organs but also migrates inside the central nervous system (CNS). Most importantly, administration of ASCs in chronic established EAE significantly ameliorates the disease course and reduces both demyelination and axonal loss, and induces a Th2-type cytokine shift in T cells. Interestingly, a relevant subset of ASCs expresses activated alpha 4 integrins and adheres to inflamed brain venules in intravital microscopy experiments. Bioluminescence imaging shows that alpha 4 integrins control ASC accumulation in inflamed CNS. Importantly, we found that ASC cultures produce basic fibroblast growth factor, brain-derived growth factor, and platelet-derived growth factor-AB. Moreover, ASC infiltration within demyelinated areas is accompanied by increased number of endogenous oligodendrocyte progenitors. In conclusion, we show that ASCs have clear therapeutic potential by a bimodal mechanism, by suppressing the autoimmune response in early phases of disease as well as by inducing local neuroregeneration by endogenous progenitors in animals with established disease. Overall, our data suggest that ASCs represent a valuable tool for stem cell-based therapy in chronic inflammatory diseases of the CNS.
PMID: 19676124 [PubMed – indexed for MEDLINE]

Stem Cells. 2009 Oct;27(10):2624-35

Adipose-derived mesenchymal stem cells ameliorate chronic experimental autoimmune encephalomyelitis.

Constantin G, Marconi S, Rossi B, Angiari S, Calderan L, Anghileri E, Gini B, Bach SD, Martinello M, Bifari F, Galiè M, Turano E,

Abstract
Budui S, Sbarbati A, Krampera M, Bonetti B
Mesenchymal stem cells (MSCs) represent a promising therapeutic approach for neurological autoimmune diseases; previous studies have shown that treatment with bone marrow-derived MSCs induces immune modulation and reduces disease severity in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. Here we show that intravenous administration of adipose-derived MSCs (ASCs) before disease onset significantly reduces the severity of EAE by immune modulation and decreases spinal cord inflammation and demyelination. ASCs preferentially home into lymphoid organs but also migrates inside the central nervous system (CNS). Most importantly, administration of ASCs in chronic established EAE significantly ameliorates the disease course and reduces both demyelination and axonal loss, and induces a Th2-type cytokine shift in T cells. Interestingly, a relevant subset of ASCs expresses activated alpha 4 integrins and adheres to inflamed brain venules in intravital microscopy experiments. Bioluminescence imaging shows that alpha 4 integrins control ASC accumulation in inflamed CNS. Importantly, we found that ASC cultures produce basic fibroblast growth factor, brain-derived growth factor, and platelet-derived growth factor-AB. Moreover, ASC infiltration within demyelinated areas is accompanied by increased number of endogenous oligodendrocyte progenitors. In conclusion, we show that ASCs have clear therapeutic potential by a bimodal mechanism, by suppressing the autoimmune response in early phases of disease as well as by inducing local neuroregeneration by endogenous progenitors in animals with established disease. Overall, our data suggest that ASCs represent a valuable tool for stem cell-based therapy in chronic inflammatory diseases of the CNS.
PMID: 19676124 [PubMed – indexed for MEDLINE]

J Neurochem. 2009 Sep;110(5):1674-84

Neuroprotective mesenchymal stem cells are endowed with a potent antioxidant effect in vivo.

Lanza C, Morando S, Voci A, Canesi L, Principato MC, Serpero LD, Mancardi G, Uccelli A, Vergani L

Abstract
Experimental autoimmune encephalomyelitis (EAE), an animal model for human multiple sclerosis, is characterized by demyelination, inflammation and neurodegeneration of CNS in which free radicals play a role. Recently, the efficacy of murine mesenchimal stem cells (MSCs) as treatment of EAE induced in mice by the encephalitogenic peptide MOG(35-55) was demonstrated. The present study analyzed some markers of oxidative stress, inflammation/degeneration and apoptosis such as metallothioneins (MTs), antioxidant enzymes (superoxide dismutase, catalase and glutathione-S-transferase), poly(ADP-ribose) polymerase-1 and p53 during EAE progression and following MSC treatment. Expression of the three brain MT isoforms increased significantly in EAE mice compared with healthy controls, but while expression of MT-1 and MT-3 increased along EAE course, MT-2 was up-regulated at the onset, but returned to levels similar to those of controls in chronic phase. The changes in the transcription and activity of the antioxidant enzymes and in expression of poly(ADP-ribose) polymerase-1 and p53 showed the same kinetics observed for MT-1 and MT-3 during EAE. Interestingly, i.v. administration of MSCs reduced the EAE-induced increases in levels/activities of all these proteins. These results support an antioxidant and neuroprotective activity for MSCs that was also confirmed in vitro on neuroblastoma cells exposed to an oxidative insult.
PMID: 19619133 [PubMed – indexed for MEDLINE]

J Neurosci Res. 2009 Aug 1;87(10):2183-200.

Stem cell-based cell therapy in neurological diseases: a review.

Kim SU, de Vellis J.

Division of Neurology, Department of Medicine, UBC Hospital, University of British Columbia, Vancouver, British Columbia, Canada. sukim@interchange.ubc.ca

Abstract
Human neurological disorders such as Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis (ALS), Alzheimer’s disease, multiple sclerosis (MS), stroke, and spinal cord injury are caused by a loss of neurons and glial cells in the brain or spinal cord. Cell replacement therapy and gene transfer to the diseased or injured brain have provided the basis for the development of potentially powerful new therapeutic strategies for a broad spectrum of human neurological diseases. However, the paucity of suitable cell types for cell replacement therapy in patients suffering from neurological disorders has hampered the development of this promising therapeutic approach. In recent years, neurons and glial cells have successfully been generated from stem cells such as embryonic stem cells, mesenchymal stem cells, and neural stem cells, and extensive efforts by investigators to develop stem cell-based brain transplantation therapies have been carried out. We review here notable experimental and preclinical studies previously published involving stem cell-based cell and gene therapies for Parkinson’s disease, Huntington’s disease, ALS, Alzheimer’s disease, MS, stroke, spinal cord injury, brain tumor, and lysosomal storage diseases and discuss the future prospects for stem cell therapy of neurological disorders in the clinical setting. There are still many obstacles to be overcome before clinical application of cell therapy in neurological disease patients is adopted: 1) it is still uncertain what kind of stem cells would be an ideal source for cellular grafts, and 2) the mechanism by which transplantation of stem cells leads to an enhanced functional recovery and structural reorganization must to be better understood. Steady and solid progress in stem cell research in both basic and preclinical settings should support the hope for development of stem cell-based cell therapies for neurological diseases.

Neurosci Lett. 2009 Jun 12;456(3):101-6. Epub 2009 Jan 17.

Regeneration and repair in multiple sclerosis: the role of cell transplantation.

Pluchino S, Zanotti L, Brini E, Ferrari S, Martino G.

Neuroimmunology Unit and Institute of Experimental Neurology (INSpe), DIBIT-San Raffaele Scientific Institute, via Olgettina 58, 20123 Milano, Italy.

Abstract
Physiological (spontaneous) and reactive (reparative) regenerative processes are fundamental part of life and greatly differ among the different animals and tissues. While spontaneous regeneration naturally occurs upon cell attrition, reparative regeneration occurs as a consequence of tissue damage. Both spontaneous and reparative regeneration play an important role in maintaining the normal equilibrium of the central nervous system (CNS) as well as in promoting its repair upon injury. Cells play a critical role in reparative regeneration as regenerating structures (cells or tissues) depend on the proliferation without (de)differentiation of parenchymal cells surviving to the injury, proliferation of stem (progenitor) cells resident in the injured tissue, dedifferentiation of mature cells in the remaining tissue, or by the influx of stem cells originating outside the damaged tissue. Considering the central role of stem and progenitor cells in regeneration, a spur of experimental stem cell-based transplantation approaches for tissue (e.g. CNS) repair has been recently generated. This review will focus on the therapeutic efficacy of different sources of somatic stem cells – and in particular on those of neural origin – in promoting CNS repair in a chronic (auto)immune-mediated inflammatory disorder such as multiple sclerosis.
PMID: 19429143 [PubMed – indexed for MEDLINE]

Duodecim. 2009;125(9):965-73

[Stem cells in therapy of multiple sclerosis]

Narkilahti S, Hovatta O, Elovaara I

Abstract
In multiple sclerosis, inflammatory autoimmune response, degeneration of the central nervous system and axonal damage eventually lead to disability. The inflammatory reaction can be controlled with current medication, whereas the neuronal and myelin damage is practically uncontrollable. Cell therapies may provide a new means to prevent nerve cell destruction and promote the regeneration of brain tissue. Bone marrow stem cell transplantation has been used as an immune response modifying therapy in severe MS. Experimental evidence of corrective and protective effects on tissues by preneuronal cells differentiated from fetal and embryonal human stem cells has been obtained in an animal model.
PMID: 19517865 [PubMed – indexed for MEDLINE]

Nat Rev Neurol. 2009 Jun;5(6):300-2

Multiple sclerosis: Hematopoietic stem cell transplantation: hope and hype.

Stangel M

Abstract
A trial of autologous hematopoietic stem cell transplantation to treat multiple sclerosis has yielded promising results, generating considerable interest within both the clinical literature and the mainstream press.the findings should, however, be interpreted with some caution, and larger, randomized trials will be required to establish the true efficacy of the approach.
PMID: 19498429 [PubMed – indexed for MEDLINE]

J Transl Med. 2009;7:29

Non-expanded adipose stromal vascular fraction cell therapy for multiple sclerosis.

Riordan NH, Ichim TE, Min WP, Wang H, Solano F, Lara F, Alfaro M, Rodriguez JP, Harman RJ, Patel AN, Murphy MP, Lee RR, Minev B

Abstract
The stromal vascular fraction (SVF) of adipose tissue is known to contain mesenchymal stem cells (MSC), T regulatory cells, endothelial precursor cells, preadipocytes, as well as anti-inflammatory M2 macrophages. Safety of autologous adipose tissue implantation is supported by extensive use of this procedure in cosmetic surgery, as well as by ongoing studies using in vitro expanded adipose derived MSC. Equine and canine studies demonstrating anti-inflammatory and regenerative effects of non-expanded SVF cells have yielded promising results. Although non-expanded SVF cells have been used successfully in accelerating healing of Crohn’s fistulas, to our knowledge clinical use of these cells for systemic immune modulation has not been reported. In this communication we discuss the rationale for use of autologous SVF in treatment of multiple sclerosis and describe our experiences with three patients. Based on this rationale and initial experiences, we propose controlled trials of autologous SVF in various inflammatory conditions.
PMID: 19393041 [PubMed – indexed for MEDLINE]

Biologics. 2008 Dec;2(4):699-705

Microenvironmental considerations in the application of human mesenchymal stem cells in regenerative therapies.

Greco SJ, Rameshwar P

Abstract
The therapeutic utilization of stem cells has been ongoing for several decades, principally in the form of bone marrow (BM) transplants to treat various hematological disorders and other immune-related diseases. More recently, stem cells have been examined as a potential therapy for a multitude of other diseases and disorders, many of which are currently untreatable. One consideration that poses a formidable task for the successful clinical application of stem cells in new disease models is the impact of the host tissue microenvironment on the desired therapeutic outcome. In vitro, stem cells exist in surroundings directly controllable by the researcher to produce the desired cellular behavior. In vivo, the transplanted cells are exposed to a dynamic host microenvironment laden with soluble mediators and immunoreactive cells. In this review, we focus on the possible contribution by microenvironmental factors, and how these influences can be overcome in therapies utilizing mesenchymal stem cells (MSCs), such as for graft versus host disease, multiple sclerosis and ischemia among others. Specifically, we examine three ubiquitous microenvironmental factors, IL-1alpha/beta(,) TNFalpha, and SDF-1alpha, and consider how inhibitors and receptor antagonists to these molecules could be applied to increase the efficacy of MSC therapies while minimizing unforeseen harm to the patient.
PMID: 19707450 [PubMed – in process]

Clin Neurol Neurosurg. 2008 Nov;110(9):889-96. Epub 2008 Mar 28.

The potential use of stem cells in multiple sclerosis: an overview of the preclinical experience.

Karussis D, Kassis I.

Department of Neurology, Laboratory of Neuroimmunology, Agnes-Ginges Center for Neurogenetics, Hadassah-Hebrew University Hospital, Ein-Karem, Jerusalem, Israel. karus@cc.huji.ac.il

Abstract
The reported neurodegeneration process in multiple sclerosis may explain the lack of efficacy of the currently used immunomodulating modalities and the irreversible axonal damage, which results in accumulating disability. Efforts for neuroprotective treatments have not been, so far, successful in clinical studies in other CNS diseases. Therefore, for MS, the use of stem cells may provide a logical solution, since these cells can migrate locally into the areas of white matter lesions (plaques) and have the potential to support local neurogenesis and rebuilding of the affected myelin. This may be achieved both by support of the resident CNS stem cells repertoire and by differentiation of the transplanted cells into neurons and myelin-producing cells (oligodendrocytes). Stem cells were also shown to possess immunomodulating properties, inducing systemic and local suppression of the myelin-targeting autoimmune lymphocytes. Several types of stem cells (embryonic and adult) have been described and extensively studied in animal models of CNS diseases. In this review, we summarize the experience with the use of different types of stem cells in the animal models of MS (EAE) and we describe the advantages and disadvantages of each stem cell type for future clinical applications in MS.
PMID: 18375051 [PubMed – indexed for MEDLINE]

Neuropathology. 2004 Sep;24(3):159-71.

Human neural stem cells genetically modified for brain repair in neurological disorders.
Kim SU.

Brain Disease Research Center, Ajou University School of Medicine, Suwon, Korea. sukim@ajou.ac.kr

Abstract
Existence of multipotent neural stem cells (NSC) has been known in developing or adult mammalian CNS, including humans. NSC have the capacity to grow indefinitely and have multipotent potential to differentiate into three major cell types of CNS, neurons, astrocytes and oligodendrocytes. Stable clonal lines of human NSC have recently been generated from the human fetal telencephalon using a retroviral vector encoding v-myc. One of the NSC lines, HB1.F3, carries normal human karyotype of 46XX and has the ability to self-renew, differentiate into cells of neuronal and glial lineages, and integrate into the damaged CNS loci upon transplantation into the brain of animal models of Parkinson disease, HD, stroke and mucopolysaccharidosis. F3 human NSC were genetically engineered to produce L-dihydroxyphenylalanine (L-DOPA) by double transfection with cDNA for tyrosine hydroxylase and guanosine triphosphate cylohydrolase-1, and transplantation of these cells in the brain of Parkinson disease model rats led to L-DOPA production and functional recovery. Proactively transplanted F3 human NSC in rat striatum, supported the survival of host striatal neurons against neuronal injury caused by 3-nitropro-pionic acid in rat model of HD. Intravenously introduced through the tail vein, F3 human NSC were found to migrate into ischemic lesion sites, differentiate into neurons and glial cells, and improve functional deficits in rat stroke models. These results indicate that human NSC should be an ideal vehicle for cell replacement and gene transfer therapy for patients with neurological diseases. In addition to immortalized human NSC, immortalized human bone marrow mesenchymal stem cell lines have been generated from human embryonic bone marrow issues with retroviral vectors encording v-myc or teromerase gene. These immortalized cell lines of human bone marrow mesenchymal stem cells differentiated into neurons/glial cells, bone, cartilage and adipose tissue when they were grown in selective inducing media. There is further need for investigation into the neurogenic potential of the human bone marrow stem cell lines and their utility in animal models of neurological diseases.
PMID: 15484694 [PubMed – indexed for MEDLINE]