Stem Cell Therapy & Multiple Sclerosis. Bernhard H.J. Juurlink 1 Professor emeritus, Department of Anatomy & Cell Biology University of Saskatchewan

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1 Volume 4: Issue 1, April 2, 2014 Stem Cell Therapy & Multiple Sclerosis Bernhard H.J. Juurlink 1 Professor emeritus, Department of Anatomy & Cell Biology University of Saskatchewan INTRODUCTION: There are essentially two types of stem cells being used in the research laboratory: embryonic stem cells and adult tissue-derived stem cells. Embryonic stem cells are derived from embryonic blastomeric cells. These stem cells can give rise to all the cell types of the body. Many people have ethical problems with the use of embryonic stem cells. Adult tissue-derived stem cells are further divided into three types: hemopoietic stem cells (HSCs), mesenchymal stem cells (MSCs), and Neural stem cells (NCCs). Few people have ethical problems with the use of adult tissue-derived stem cells. Adult stem cells can be obtained from the same individuals to be treated with the advantage being that such autologous stem cells will not be recognized as foreign by the individual s immune system. A brief history of adult stem cells is given in Appendix 1. Both HSCs and MSCs have been used in clinical trials to treat multiple sclerosis (MS). Stem cell therapy was first used in rodent models of experimental allergenic encephalomyelitis (EAE) and showed great promise in ameliorating EAE. Although many researchers in the area of MS regard EAE as a good model of MS, there is considerable skepticism and, to me, evidence suggests that EAE is a good model only of acute disseminated encephalomyelitis, as some others also think (Baker, D. & S.J. Jackson Models of multiple sclerosis. Advances in Clinical Neurosciences & Rehabilitation 6:10-12). So the thinking was that stem cell treatments seem to work in EAE, let us see if it works with MS. This is the classic rationale of therapeutic interventions in the absence of effective treatments, let us see if it will work. The first stem cells used to treat human MS were HSCs. MSCs have also been used in MS therapy, but NSCs have not. MULTIPLE SCLEROSIS AND AUTOLOGOUS HEMOPOIETIC STEM CELL TRANSPLANTATION: Starting in the early 1990s there were a series of small clinical trials 1 Dr. Juurlink can be reached at Dr. Bernhard Juurlink Bernhard@nationalccsvisociety.org if you have any questions or comments about this series.

2 whose objectives were to eliminate the immune system that was attacking myelin in people with MS and replace the immune system with cells derived from HSCs (see: Fassas, A. & G.L. Mancardi Autologous hemopoietic stem cell transplantation for multiple sclerosis. Is it worthwhile? Autoimmunity 41(8): ; Atkins, H.L. & M.S. Freedman Hematopoietic stem cell therapy for multiple sclerosis: Top 10 lessons learned. Neurotherapeutics 10:68-76). The essential thinking was that if one could eliminate the immune cells (especially the T lymphocytes) attacking myelin and then reconstitute the immune system with HSCs one might stop the progression, and even reverse, the MS disease. If the primary problem lies within the immune system, then this would be a reasonable approach. This may not be the case. Although it is clear that the immune system of people with MS is predisposed to attack myelin, it may well attack myelin because of a neurodegenerative event that damages myelin and its associated cell, the oligodendrocyte (see: Juurlink, B.H.J Scientific hubris and the tunnel vision driven by looking where the light is brightest. In: Editors: C. Rangacharyulu, Emmanuel Haven and Bernhard H.J. Juurlink, The World In Prismatic Views: Proceedings of the Second Interdisciplinary CHESS Interactions Conference, World Scientific Publishing). If this is the case, then replacing the immune system does nothing for a putative neurodegenerative insult. One of the problems in HSC therapy is the initial elimination of the immune system since the chemicals (and/or x-irradiation) used have adverse effects, including neurotoxic effects. Furthermore, during the time the immune system is eliminated, and before it is reconstituted, the body is very susceptible to infection and is at increased risk of developing cancer. Nevertheless, small clinical trials were initiated. The initial mortality rates were high up to 20%. With adjustments in procedures the mortality rates have been brought down to 1-3%, depending upon clinical trial and procedural detail. To date, more than 600 people have undergone HSC treatment to treat autoimmune diseases, mainly MS. The treatment involves isolating HSCs followed by eliminating the immune system and bone marrow cells and finally introducing HSCs to repopulate the bone marrow and replenish the immune system. Elimination of HSCs results in increased susceptibility to infection, reactivation of latent viruses (e.g., Herpes zoster [chicken pox/shingles virus], Epstein-Barr, Herpesvirus 6, cytomegalovirus) that may also involve brain damage. The more intensive approaches used in eliminating the immune system results in better outcomes from HSC treatment as measured by progression of the Expanded Disability Status Score (EDSS), but also increases mortality and non-mortal adverse affects (morbidity). Currently, 45% of HSC-treated people with secondary progressive MS who are younger and have relatively low EDSS were found to have stable EDSS for 5 years post-treatment. But, importantly, note that the data are from non-randomized trials with no control groups a deficit that neurologists are keen to point out is present in the majority of the angioplasty clinical trials used to treat CCSVI (i.e., obstructed venous return from the brain and spinal cord). Furthermore, this incidence of being progression-free following HSC treatment decreases with longer posttreatment time periods. It is important to point out that the initial favourable number for HSC treatment outcomes is derived from carefully selecting patients who have low EDSS, who were younger and had been diagnosed with MS for only a few years. Patients with higher EDSS (> 6) and having the disease longer do not fare as well. Predisposition for autoimmune diseases does not disappear with autologous HSC treatment; indeed, 10% of people treated develop another autoimmune disease within 2 years. Also, brain atrophy is not affected by the HSC treatment, again indicating that the immune response is likely secondary in persons with MS.

3 I think the jury is out on whether immune depletion followed by HSC transplantation results in better outcomes, and if better outcomes, the question arises if the risk of mortality or increased morbidity is worth it. MULTIPLE SCLEROSIS (MS) AND MESENCHYMAL STEM CELL THERAPY: One of the problems in MS is that axons (nerve fibres) within the brain and spinal cord become demyelinated and many of the associated oligodendrocytes (myelin-forming cells) die. The initial thinking for MS was that adult tissue-derived stem cells could be used to regenerate new oligodendrocytes that would then go on to myelinate the axons that had previously been demyelinated. Two types of adult tissue-derived stem cells are being examined experimentally in EAE animal models as possible therapies for MS: NSCs and MSCs. Stem cells have been shown to have only a modest positive effect on remyelination in various rodent demyelination models (Reekmans, K. et al Stem cell therapy for multiple sclerosis: preclinical evidence beyond all doubt. Regenerative Medicine 7(2): ). Although NSCs have been extensively used in this research, it is unlikely that autologous NSCs have a future in MS therapy since it is unlikely anyone is willing to give up a bit of brain tissue to provide the initial NSCs. As mentioned in the Appendix, there are, however, neural stem cells with a more restricted ability to differentiate these are the olfactory ensheathing cells (OECs) and these can be obtained from the olfactory nerve as it runs from the upper part of the nasal cavity to the brain. In contrast to HSC therapy, the use of MSC does not require the elimination of the bone marrow cells and the immune system, and from this perspective it is a much safer therapy. Unexpected Findings with Stem Cell Therapy to Treat EAE: The ability of stem cells to promote remyelination in rodent EAE models has been disappointing; however, there was a totally unexpected finding introducing stem cells to mice with EAE ameliorated inflammation and other aspects of the immune response. Thus, even when stem cells do not make it to the lesion sites in EAE there is a down-regulation of immune response ameliorating the clinical symptoms of EAE. How stem cells modulate inflammation and immune responses is completely unknown. Nevertheless, clinical trials using stem cells in people with MS are underway. So here we have an example of: We have no idea what the mechanism of action is but it seems to work in EAE; hence, let us try it in humans with MS. Once more, quite a difference in attitude to that seen towards angioplasty to correct obstructed venous return. Whether a therapeutic approach to MS is rational seems to depend upon who initiates the approach and not due to understanding the underlying science. Clinical Trials Using Autologous MSCs to Treat MS: I could find several groups publishing on clinical trials. The first one, a phase 0 trial (examines safety on very small groups of patients) initially reported treating 10 patients with progressive MS who were unresponsive to or ineligible for conventional treatments (Bonab, M.M. et al Does mesenchymal stem cell therapy help multiple sclerosis patients? Report of a pilot study. Iranian Journal of Immunology 4(1):50-57). This small trial was simply a feasibility study. The authors subsequently reported on a slightly larger phase I trial (again examining safety) involving 22 patients with progressive MS (Bonab, M.M. et al Autologous mesenchymal stem cell therapy in progressive multiple sclerosis: an open label study. Current Stem Cell Research & Therapy 7(6): ). I only have access to the abstract where they report only minor adverse effects and, over a year, the average EDSS scores increased from 6.1 to 6.3, with improvement in scores in 4, deterioration in scores in 6, and no change in 12. This trial, without a control group, basically looked at safety and concluded that further studies must be performed.

4 The design of a small MSC therapy clinical trial on secondary progressive MS patients is described in 2011 (Connick. P. et al The mesenchymal stem cells in multiple sclerosis [MSCIMS] trial protocol and baseline cohort characteristics: An open label pre-test:post-test study with blinded outcome assessments. Trials 12: with the first efficacy results reported in 2012 (Connick, P. et al Autologous mesenchymal stem cell therapy for treatment of secondary progressive multiple sclerosis: an open label phase 2A proof-of-concept study. Lancet Neurology 11(2): ). The blinding in the assessment of outcomes had to do with the fact that the assessors did not know if they were assessing patients in the pre-treatment or post-treatment groups, but the assessors clearly knew that the patients were undergoing an MSC therapy trial and, as well, the patients knew they were in the treatment group. This trial only had 10 patients, but was labeled a phase IIA trial since it examined safety as well as efficacy. Typically, phase II trials enroll between 100 and 300 patients. Fundamentally, because of the low number, the trial could only examine for safety. The authors reported minor adverse effects following transfusion of the autologous MSCs. They also reported significant improvement over 12 months in visual function and optic nerve diameter and a significant reduction in EDSS progression, but no significant change in the Multiple Sclerosis Functional Composite Score (MSFCS) nor changes in depression, cognitive function, lesion volume, or brain volume. The authors did not mention the positive effects could be attributed to placebo effects, but did indicate that randomized clinical trials are needed to verify these changes. There are two additional phasei/ii trials reported (Karussis, D. et al Safety and immunological effects of mesenchymal stem cell transplantation in patients with multiple sclerosis and amyotrophic lateral sclerosis. Archives of Neurology 67(10): ; Yamout, B. et al Bone marrow mesenchymal stem cell transplantation in patients with multiple sclerosis. Journal of Neuroimmunology 227: ). Both reported minor adverse effects and improvements in EDSS over the first 6 months post-treatment but with no statistical analyses. The report by Yamout et al. found that the apparent improvement in EDSS was no longer seen after 12 months. CONCLUDING REMARKS: HSC Therapy: HSC therapy appears most effective in relatively young, recently diagnosed MS patients who have a low EDSS. Because of the need to deplete the endogenous immune system for HSC treatment, there is a high risk of severe adverse effects, including a current 1-3% chance of death, a 10% chance of developing another autoimmune disease and a reasonable possibility of other adverse effects, including brain damage. MSC Therapy: In contrast, the evidence suggests that MSC therapy usually is only associated with minor adverse effects, although a transient encephalopathy with seizures was reported for one patient. The minor adverse effects include transient skin rashes and/or transient itchy scalp. In addition, upper respiratory and urinary infections were reported in a few subjects, but it is likely these infections had little to do with the treatment. To date, it appears that there may be benefits for the treatment, although only short-term results have so far been reported. The reason for the purported effects are unknown but it is assumed, but not demonstrated, that somehow MSC treatment promotes tissue recovery in lesions and it is also assumed, with some evidence, to be related to modulation of immune function. Thus, it appears that the effects of stem cell therapy is somewhat similar to the classical immunomodulating therapies: the interferon beta-1s

5 and copaxone. Whether the purported benefits are long-lasting is unknown at the moment, nor is it known if stem cell therapy influences disease progression. Commentary: The use of MSCs to treat MS appears to be another example of the classical it seems to work in EAE; therefore, let us run clinical trials with MS patients. Of course, this type of approach is only rational if it is driven by neurologists. That angioplasty to treat obstructed venous return from the brain and spinal cord seems to work in many people with MS; therefore, let us run clinical trials is, in contrast, deemed completely irrational, without any scientific bases, since it originates with vascular surgeons rather than a neurologists. APPENDIX 1 The first adult tissue-derived stem cells identified were hemopoietic stem cells. These stem cells were isolated and identified by Drs. Till and McCulloch in 1963 at the University of Toronto. It is these hemopoietic (or hematopoietic) stem cells that are used to regenerate the hemopoietic system (including the immune system) following complete destruction of the bone marrow as a treatment for some cancers (certain leukemias and lymphomas). In these cases normal hemopoietic stem cells are collected from the bone marrow (or even blood) of the affected individuals followed by eradication of all bone marrow cells (including the cancer cells) before repopulation of the bone marrow by the hemopoietic stem cells. In 1970, the Russian scientist Dr. Friedenstein and his colleagues demonstrated that bone marrow also contained stem cells that could give rise to bone cells, other cells as well as hemopoietic stem cells these cells became known as mesenchymal stem cells (MSCs). In 1992 Drs. Reynolds and Weiss of the University of Calgary isolated neural stem cells (NSCs) from the rodent adult central nervous system. There are also neural stem cells with a more restricted ability to differentiate these are the olfactory ensheathing cells (OECs). OECs normally form the non-myelinating glial (support cell) covering of the olfactory nerve axons. The olfactory nerve forms part of the peripheral nervous system and sends olfactory information to the olfactory part of the brain. The olfactory sensory neurons that lie in the roof of the nasal cavity give rise to the olfactory axons these sensory neurons regenerate themselves and have a lifespan of about 7 weeks or so. It is a relatively simple procedure to obtain a bit of olfactory nerve and grow up the OECs in cell culture. The damaged nerve fibres will regenerate over a matter of weeks. A colleague of mine in the Department of Anatomy & Cell Biology at the University of Saskatchewan, Dr. Ron Doucette, not only isolated these OECs but further demonstrated that under the right conditions they could myelinate axons (Devon, R. & R. Doucette Olfactory ensheathing cells myelinate dorsal root ganglion neurites. Brain Research 589(1): ). To date, the myelinating capacity of OECs has only been examined in the context of spinal cord injury-associated demyelination. We now know that almost every tissue of the body contains stem cells that can give rise to many different cell types and we are just beginning to understand some of the factors that cause stem cells to give rise to particular cell types. 2 2 Acknowledgements: I thank Sandra Birrell for going over this manuscript.