USE OF STEM CELLS TO TREAT MULTIPLE SCLEROSIS





























INTRODUCTION

What is Multiple Sclerosis?


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Multiple Sclerosis is a neurological inflammatory disease. It is characterized by the loss of myelin sheaths and cells that produce myelin (1). The early part of the disease is dominated by the inflammatory process, but later in the course of the disease neurodegeneration predominates. It causes cognitive defects in many vital processes like attention, memory, visuospatial abilities and is a long standing cause of disability in the younger and older populations (2). During the course of the disease, the symptoms usually get worse.






Causes


Despite the progress, it is still hard to pinpoint one cause for the disease. Current view implicates a multifactorial setting of risk factors including both genetic susceptibility and environmental factors. Presence of several alleles have correlated with increased risk of developing multiple sclerosis. The concordance rate for Monozygotic Twins is about 20-30% whereas the concordance rate for dizygotic twins is 3-5% (3). For environmental factors a low vitamin D level, low exposure to the sun and the Epstein Barr virus are being taken to be few of the most prominent ones that increase the risk (4). Nonetheless, none of these are sufficient to explain the pathogenensis and causation of the disease.

EPIDEMIOLOGY AND CURRENT TREATMENT OPTIONS

Epidemiology

There is an evident gender difference, with females being more susceptible than men. In Canada, the ratio is now approaching 3.2:1 (5). The reason is not yet clear; it has been speculated that it is due to the presence of certain triggers in females (5). The general incidence rates are highest in the extreme latitudes in the Northern and Southern hemisphere. This has been speculated to be due to genetic predispositions or because of the presence of an infectious agent that maybe endemic in these regions (6).

Current Therapeutics

Therapeutic options involve curbing the effects of the disease to a minimum. B-Interferons are administered to reduce relapses and also to slow the progress of the disease with patients relapsing-remitting Multiple Sclerosis. It has anti-inflammatory effects. Corticosteroids which are potent anti-inflammatory and immunosuppressive drugs repair any damages in the blood-brain barrier and induce T-cell apoptosis. Administration of these limit the inflammation during an acute relapse (2). Other medications involve dealing with secondary problems caused by the disease like depression, fatigue, sexual dysfunction and cognitive defects (7).

RESEARCH DIRECTIONS –STEM CELLS

None of the above-mentioned therapeutics provide a cure for the disease. Immune treatments can reduce individual relapses but have no impact on patients with the progressive disability (8). This therapeutic impotence has stimulated much research and a striking possibility that is being considered now is stem __cell__ therapy. What the researchers are looking for is something that tackles the abnormal immunoresponse and enhance repair or cell replacement (9). Most current therapies whereas they do concentrate on improving the abnormal immune response, but they fail to address the failure of repair mechanisms (10).
As the disease targets only the oligodendrocytes and the axons are largely spared, this saves us from rebuilding the circuitry in the brain. With the help of MRI scans exogenous stem cells can be injected into the lesions, where they can generate new myelin (8).


Embryonic Stem cells have the distinct ability to differentiate into cell types of all lineages but the translation of this into clinical trials is walled by ethical issues and national legislation limits (12). The use of induced pluripotent cells from somatic cells is still in its infant stages of research and the safety of doing so has not been established yet. Adult stem cell of haemopoietic origin have been used in neurological disorders like ALS. These stem cells however do not acquire a neural phenotype after implantation and at best they are a source of neurotrophic factors to the damaged CNS (12). Neural Precursor Cells are also a viable option and have shown tremendous results in trials involving animal models. But the difficulty in obtaining fetal neural tissues and technical problems in order to expand to large scale yields under good manufacturing practice conditions, has been an obstacle towards clinical translation (12).

MESENCHYMAL STEM CELLS

Theoretically, the problems can be solved with a therapy that can promote remyelination and also have the ability for cell replacement or fostering of endogenous neurogenesis, to replenish the damaged neural networks (11).
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Proposed mechanisms of action of MSCs in neurological diseases (A) Intravenously injected MSCs (1) can reach the CNS where, after extravasation, they decrease proliferation of microglia (2), protect neurons (3) from degeneration occurring after inflammatory, ischaemic, and oxidative injuries, promote remyelination through the recruitment of oligodendrocytes (4), and inhibit proliferation of astrocytes involved in gliotic scarring (5). Interaction between MSCs and local neural precursors (6) can foster endogenous neurogenesis. (B) After intravenous injection, most MSCs are trapped in the lungs (7), where they are induced to release regulatory cytokines involved in the suppression of inflammation, possibly through interaction with local cells such as resident macrophages (8). (C) MSCs can also migrate to the lymph nodes, where they have several interactions with immune cells: they inhibit proliferation and differentiation of B cells (9), suppress proliferation of T cells (10), and inhibit maturation of dendritic cells (11) and subsequent antigen presentation to T cells. MSCs=mesenchymal stem cells. Image and caption from (Ucceli, Laroni and Freedman, 2011)





Bone marrow derived mesenchymal cells have been labeled as a viable option as they are involved in tissue repair by mechanisms which are completely apposite to Multiple Sclerosis. These cells cannot trans differentiate into oligodendrocytes but have indirect means to promote remyelination. These cells have pronounced immune-modulating properties and secrete a range of neuroprotective factors. These cells can reduce gliotic scar formation and can possibly fuse with cerebellar Purkinje cells to offer protection from further degeneration (13). They can produce therapeutic effects similar to Neural precursor cells and because of their low immunogenicity they have been successfully used in xenogeneic settings (human MSCs in mice). Standards for the use of Neural Precursor cells have not been met so as of now the best option for successful clinical use is autologous Mesenchymal cells (12).


DEVELOPMENT OF A CLINICAL MODEL

Animal Models

There has been a lot of theorizing and now the ideas are being translated into clinical use. Recent studies have demonstrated that bone-marrow derived mesenchymal cells promote functional recovery in mice with allergic encephalomyelitis (EAE) (14). The injected cells accumulated in the CNS and increased oligodendrocyte lineage cells in lesion areas. The overall extent of damage in the CNS was reduced. The increase in oligodendrocyte lineage reflect BM-MSC induced changes. Even the immune responses of the mice were influenced as inflammatory T-cells, interferon gamma producing cells and their associated cytokines were reduced. This is one of the many examples that are indicative of the fact that Bone-marrow derived mesenchymal cells represent a viable option for therapeutic approaches (14).

Human Trials

Given the amount of studies and animal experimental models that attested the safety of BM-MSCs, it prompted the induction of a pilot study of phase I clinical trials using autologous ex-vivo expanded bone marrow derived Mesenchymal Stem Cell to treat patients with advanced Multiple Sclerosis (13).
The paper by Yamout et al 2010. cites clinical trials using autologous ex-vivo expanded bone marrow derived Mesenchymal Stem Cell to treat patients with advanced Multiple Sclerosis (13).
Patients were selected on the basis of being diagnosed with Multiple Sclerosis and failure of treatment with one of the standard therapies and progression to advanced disability. The patients then underwent bone marrow aspiration (20ml) from the posterior iliac crest. Post-injection, the patients then underwent clinical assessment and laboratory tests at baseline, 3 months, 6 months and 12 months. Three out of the ten selected participants could not grow adequate number of BM- MSCs . This could not be connected to the patients age, sex, disease duration or even treatments applied. However, due to the small number of patients in our trial, a negative effect of previous therapies like interferons or immunosuppresants cannot be ruled out. The exact reason will need further studies to clarify. One of the patients suffered from transient encephalopathy, which was speculated to be due to lysis of high numbers of injected cells within the cerebrospinal fluid.
The other seven showed functional and subjective improvement in their neurological status even 3-6 months after the procedure. Six out of the seven patients showed improvement on different components of the EDSS (Expanded Disability Scale Score) and MSFC (Multiple Sclerosis Composite Scores). Also Clinical improvement was maintained overall at one year for the four patients that were subjected to longer follow-up.

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But despite the fact that clinical results showed improvement or stabilization, the MRI studies showed that the disease was progressing. There was increase in lesion numbers in three out of seven patients. There was an increase in the number of new enhancing lesions in three out of seven patients. This increase in lesion number and enhancement could have been due to various reasons. It could be due to reactive inflammation secondary to cell lysis byproducts. Other possible reasons include immunological effect of stem cells or repair mechanisms within the central nervous system. It could also very well be due to failure of BM-MSC treatment in preventing ongoing inflammation due to the disease.

CONCLUSION


This was just a pilot study in order to study the safety and feasibility of the procedure. The results showed a safety profile of up to one year. Then again, the numbers were small and possible long term side-effects were not analyzed. Mesenchymal cells have been used in different treatments and have showed a good safety profile in many of them; i.e hematological malignances, kidney disease and inherited leukodystrophies. But even apart from safety profile, there are many other things that need to be considered. Questions like preferred way of injection and how many cells are needed to be injected in order to get the therapeutic outcome and should this be used only in advanced cases or in relapsing remitting cases at an earlier stage, can only be answered after the exact mechanism of action of BM-MSC in multiple Scelrosis is found out. The major drawback of this study is in its numbers and for phase II of this study there should be an international concerted effort which will more likely produce more fruitful answers and more future directions of research. Long term safety concerns are still present. There is still fear that MSC’s might induce tumour growth or might undergo carcinogenic transformation and more studies need to be done to eradicate those fears. But overall the preclinical studies support the use of MSC’s in Multiple Sclerosis.
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Table from ( Uccelli, Laroni & Freedman, 2011)


The Multiple Sclerosis Research Centre of New York and the International Cellular Medicine Society have jointly announced the approval of their study in December, 2011 that will use mesenchymal stem cell-derived NPC’s harvested from the patient’s own marrow (15). This will be a three year study and the patients will be injected at three month intervals. This is just one of the many studies yet to come that will investigate the role that Mesenchymal Stem Cells can play in the plight to find an absolute cure for Multiple Sclerosis.


See Also


1) Wikipedia - Multiple Sclerosis
2) What is Multiple Sclerosis? - Youtube link for basic understanding of Multiple Sclerosis
3) Cure for Multiple Sclerosis - Youtube link for a presentation about MSC's as a viable treatment for Multiple Sclerosis
4) Multiple Sclerosis Society
5) Multiple Sclerosis International Federation
6) Multiple Sclerosis Society of Canada

Further Reading

1) Theories of Origins and Risk Factors of Multiple Sclerosis
2) Pathophysiology of Multiple Sclerosis
3) MS clinical symptoms and diagnosis
4) MS alternative therapies
5) Multiple Sclerosis Modifying treatments





















REFERENCES
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2) Crayton, H.J., & Rossman, H.S. (2006). Managing the symptoms of multiple sclerosis: a multimodal approach. Clinical Therapeutics, 28(4), 445-460
3) Keegan, B.M., & Noseworthy, J.H. (2002). Multiple Sclerosis. Annual Review of Medicine, 53, 285-302.
4) Paulig, M. (2010). What causes multiple sclerosis. Nervenheilkunde, 29(12), 820-824.
5) Zajicek, J. (2007) The epidemiology of multiple sclerosis. Journal of Neurology, 254(12), 1742-1742
6) Weinshenker, B.G. (1996) Epidemiology of multiple sclerosis. Neurological Clinics, 14(2), 291-292
7) Ferreira, M.L. (2010). Cognitive defects in multiple sclerosis: a systematic review. Arquivos de Neuro-psiquiatria, 68(4), 632-641.
8) Scolding, N. Adult stem cells and multiple sclerosis. (2011). Cell proliferation, 44, 35-38.
9) Karussis, D., & Kassis, I. (2008). The potential use of stem cells in multiple sclerosis: An overview of the preclinical experience. Clinical Neurology and Neurosurgery, 110(9), 889-896.
10)Ben Hur, T. (2011). Cell therapy for multiple sclerosis. Neurotherapeutics: The journal of the American society for experimental Neurotherapeutics, 8(4), 625-642.
11)Greenberg, B.M., & Calabresi, P.A. (2011). Future research directions in multiple sclerosis therapy. Seminars in Neurology, 28(1), 121-127.
12)Uccelli, A., Laroni, A., & Freedman, M.S. (2011). Mesenchymal stem cells for the treatment of multiple sclerosis and other neurological diseases. The Lancet Neurology, 10(7), 649-656.
13)Yamout, B., Hourani, R., Salti, H., Barada, W., El Hajj, T., Al Kotoubi, A., …Bazarbacchi, A. (2010). Bone marrow mesenchymal stem cell transplantation in patients with multiple sclerosis: A pilot study. Journal of Neuroimmunology, 227(2), 185-189.
14)Bai, L., Lennon, D.P., Eaton, V., Maier, K., Caplan, A., Miller, S.D., & Miller, R.H. (2009). Human bone marrow-derived mesenchymal stem cells induce Th2-polarized immune response and promote endogenous repair in animal models of multiple sclerosis. Glia, 57(11), 1192-1203.
15)Gilbert, T. (2011, Nov 21). MSRCNY receives approval for groundbreaking stem cell trial in multiple sclerosis. Retrieved from http://www.msrcny.org/news/stem-cell-trial-approved-0