Multiple Sclerosis and Stem Cells

By Sonika Singh PhD candidate, University of Nottingham

Multiple Sclerosis (MS) is a chronic and inflammatory disease based on autoimmunity[1], mainly affecting the central nervous system (CNS) in young white adults[2]. MS is a disease which involves damage to the myelin sheath, that is a lipoprotein-based insulation of the axons. This sheath is essential for the electrical activity and saltatory conduction of nerve impulses and is an important part of the nervous system [2]. Areas of inflammation, axonal loss, demyelination and gliosis, occurring throughout the brain and spinal cord are the distinctive features of MS [3].

MS is pathologically characterised by the development of white matter (WM) lesions that possess multifocal, demyelinating and inflammatory characteristics [4]. Recurrent inflammation in the CNS results in the symptoms of MS. Oligodendrocytes are the cells that make up the myelin and in the case of its damage or inflammation, the nerve conduction gets disrupted. This causes the nerves to lose their function and results in the neurologic symptoms characterising MS [2]. Although MS has been considered to be a condition affecting the WM, recent studies have identified the involvement of grey matter as well [4].

The best accepted cause of the disease postulates that the antigens of myelin are presented to appropriate T-cells by macrophages. This activates the proliferation of T-cells. These cells cross the blood-brain-barrier (BBB) by interacting with the intercellular adhesion molecules and then release cytokines that further damage myelin and sustain the auto-immune response [5]. These subsequent events result in inflammation and the formation of plaques in the CNS, which are observed as lesions on magnetic resonance images (MRI).

Some forms of systemic infection may result in up-regulated adhesion molecules on the endothelial surface of brain and spinal cord, allowing entry of leukocytes into the CNS. This cascade of events results in the formation of acute inflammatory, demyelinating lesions [6].

The treatment of multiple sclerosis has changed, rather than evolved, over the last 20 years. Disease-modifying therapies are an essential requirement for MS patients. The goals of such therapy involve shortening the duration of acute exacerbations, decrement in their frequency and provision of symptomatic relief [7]. Such treatments are aimed at the maintenance of function and improvement in quality of life!

The accurate therapy for each MS sufferer, basically involves getting the right disease-modifying therapy at the right time! This might involve the conventional first-line or second-line medications, including Methylprednisolone for acute relapses.

Autologous Hematopoietic Stem Cell Transplantation (AHSCT) has opened new avenues for treatment of patients suffering from MS. The emergence of multipotent Mesenchymal Stem Cells (MSCs) as a potent cellular therapy for MS seems to be quite promising. On the basis of triumph in treating experimental autoimmune encephalomyelitis (EAE) mouse models, use of MSCs has progressed into clinical trials for MS. Therapy with transplantation of stem cells is an innovative and emerging research focuses to develop new and enhanced treatments for MS. As mentioned in the press releases, the transplantation of stem cells might be able to ‘freeze’ disease progression in MS.

Hematopoietic stem cells (HSC) are multipotent stem cells. The first report providing information about a bone marrow transplant was published by McAllister and colleagues. The allogenic transplant was performed in a chronic myelogenous leukaemia patient with MS. The patient showed significant improvements in MS brain lesions [8]. Patients suffering from active RRMS, not responding to conventional therapies and undergoing HSCT, experience reduced disease progression, decreased relapses as well as suppression of inflammatory MRI activity [9].

Stem cell therapy can ‘’reboot’’ the immune system. The mechanism of action involves neuro-regeneration, immunomodulation and neuroprotection [10]. Superficially, the procedure involves the isolation of MSCs from adult bone marrow, followed by ex-vivo expansion and re-infusion.

A pilot study of MSC transplantation conducted on MS patients resulted in improved EDSS showing stability and progression in 14.28% of participants [10]. A Phase II randomized double-blind, placebo-controlled crossover clinical trial has depicted lower mean cumulative number of lesions in patients receiving MSCs as compared to those receiving placebo [11].

Transplantation of autologous HSCs is being offered to a small number of MS patients outside of clinical trials, following the failure of conventional therapies and when further disease progression is inevitable!

The procedure involves ‘Mobilisation’ of stem cells from the bone marrow into the blood stream, followed by ‘Harvesting’ of stem cells by apheresis. The harvested stem cells are expanded and ‘Cryopreserved’ for the transplantation. Conditioning ‘Chemotherapy’, which is myeloablative or non-myeloablative, eliminates the immune system, expectantly destructing cells involved in MS disease activity. The isolated autologous stem cells are infused after a certain time, leading to engraftment.

The procedure requires the involvement of a neurologist, specialised in Multiple Sclerosis. Also, a specialised Hematologist and AHSCT multidisciplinary team will be involved. The criteria for this MS treatment, involves continued relapses in spite of conventional therapies, MRI disease activity, EDSS lower than 6.0 and a short disease course.

The side-effects involve being susceptible to infections due to being immune-compromised, before the immunity is reassembled by the stem cells. There will be side-effects associated with chemotherapy and there is a possibility of developing autoimmunity. The long-term side effects include lower fertility or early menopause. Malignancies and small death percentages are an add-on!

Recuperation from such an aggressive and complicated technique will, obviously, take time!

This therapy is a germinating research area but so far a finite number of small-scale clinical trials have been conducted. A review published by Radelli and colleagues summarises the results of 23 AHSCT clinical trials for MS [12]. The trials included 538 MS patients of which 62% had primary or secondary progressive MS. However, the recent trials have included relapsing MS patients. The review highlighted higher success rates of the treatment in patients with inflammatory disease activity, lower EDSS and short disease duration. Follow-up of two years after treatment, depicted no disease progression for 36 to 100% patients. The studies observing progression of disease over long-term, depicted an increase in patients whose disease progressed giving an idea of continued MS disease activity. This hints that AHSCT might prevent continued disease progression without reversal of subsisting damage!

Other clinical trials like HALT-MS, involved 24 people among whom 96% had side effects. 69% showed no progression over a period of five years. In addition, Imperial College researchers analysed AHSCT data in 281 progressive MS patients treated between 1995 and 2006. The ones who did the best (i.e. were free of disability progression) were young and had RRMS. There was an occurrence of eight deaths and they were considered to be due to the treatment.

A meta-analysis conducted by Sormani and colleagues summarised evidence on AHSCT following immune-ablative therapy, for the management of aggressive and treatment-refractory MS. The analysis included fifteen published studies (764 transplanted patients) between 1995 and 2016 for any form of MS. Transplant-related Mortality (TRM) was found to be significantly higher in older studies. Higher baseline EDSS had a significant association with high TRM. In addition, the rate of progression was calculated to be 17.1% and 23.3% at two and five years, respectively. With reference to no evidence of disease activity (NEDA), at two years the pooled proportion was found to be 83% and, 67% at 5 years [13].

Therefore, the surfacing evidence on this therapy for MS signifies a large benefit/risk profile. Early results do come with encouragement as well as noteworthy improvements! However, there is an essential requirement of longer term clinical trials to assess the efficacy and safety of stem cell therapies.

References

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Rovira, À., C. Auger, and J. Alonso, Magnetic resonance monitoring of lesion evolution in multiple sclerosis. Ther Adv Neurol Disord, 2013. 6(5): p. 298-310.

Confavreux, C., et al., Relapses and progression of disability in multiple sclerosis. N Engl J Med, 2000. 343(20): p. 1430-8.

Trip, S.A. and D.H. Miller, Imaging in multiple sclerosis. J Neurol Neurosurg Psychiatry, 2005. 76 Suppl 3: p. iii11-iii18.

Halpern, R., et al., Comparison of adherence and persistence among multiple sclerosis patients treated with disease-modifying therapies: a retrospective administrative claims analysis. Patient Prefer Adherence, 2011. 5: p. 73-84.

Frohman, E.M., M.K. Racke, and C.S. Raine, Multiple sclerosis–the plaque and its pathogenesis. N Engl J Med, 2006. 354(9): p. 942-55.

Goldenberg, M.M., Multiple sclerosis review. P t, 2012. 37(3): p. 175-84.

Jeffery, D.R., Failure of allogeneic bone marrow transplantation to arrest disease activity in multiple sclerosis. Multiple Sclerosis Journal, 2007. 13(8): p. 1071-1075.

Mancardi, G. and R. Saccardi, Autologous haematopoietic stem-cell transplantation in multiple sclerosis. Lancet Neurol, 2008. 7(7): p. 626-36.

Yamout, B., et al., Bone marrow mesenchymal stem cell transplantation in patients with multiple sclerosis: a pilot study. J Neuroimmunol, 2010. 227(1-2): p. 185-9.

Llufriu, S., et al., Randomized placebo-controlled phase II trial of autologous mesenchymal stem cells in multiple sclerosis. PLoS One, 2014. 9(12): p. e113936.

Radaelli, M., et al., Autologous Bone Marrow Transplantation for the Treatment of Multiple Sclerosis. Current Neurology and Neuroscience Reports, 2014. 14(9): p. 478.

Sormani, M.P., et al., Autologous hematopoietic stem cell transplantation in multiple sclerosis: A meta-analysis. Neurology, 2017. 88(22): p. 2115-2122.