Bone marrow stem cell therapy in multiple sclerosis: potential mechanisms of repair and protection

Multiple sclerosis - MS - is a disease of the brain and spinal cord that affects 2.5m people worldwide, costing the EU economy E9 billion/year, from the consequences of progressive neurological disability. It usually starts with episodes of temporary relapse followed by periods of remission, but over 80% of patients develop permanent, progressive disability; 40% need a wheelchair within 10 years. There are no treatments that reverse, halt or even slow progressive disability in MS.
Stem cell therapy offers new possibilities for reducing disability in this incurable disease. Such benefits would have huge personal impact for patients, and also serious positive economic implications. Urgency in pursuing authentic stem cell therapies also lies in countering the deceptive attraction of unregulated commercial stem cell clinics, which take large sums of money from desperate patients for dubious and occasionally hazardous 'treatments'.
We have for some years explored the potential of human bone marrow-derived [BM] stem cells in relation to MS, initially in the laboratory, and lately in a small ('phase 1') clinical trial. We concentrate on these cells for many reasons. They are relatively accessible; they appear safe; and our and other studies have confirmed that they have a wide range of valuable therapeutic properties.
There are various sub-types of stem cell present within BM, and they appear to possess many valuable capacities of potential benefit for MS. BM stem cells dampen inflammation. They stimulate other repair cells present in the brain and spinal cord, they promote tissue repair, and they secrete growth factors - which protect brain cells against injury. Also, after injection into a vein, they successfully infiltrate the brain and spinal cord (a vital property relating to any neurological disease, where access to affected brain tissue is a serious hurdle). Last but not least, patients are treated using their own BM cells, avoiding the serious difficulties of tissue rejection.
We hypothesise that BM cell therapy in longstanding MS offers durable benefit. We believe these cells help in multiple ways, and that more than one stem cell type is involved in the therapeutic effect.
In Bristol, we recently completed one of the first feasibility/safety trials in the world of reparative BM cell therapy in 6 patients with chronic MS (www.nature.com/clpt/journal/v87/n6/full/clpt201044a.html). Safety was confirmed, and patients appeared to stabilise (though in such a relatively short term study, this must be viewed as unproven). Intensive repeated tests, measuring nerve conduction in various pathways in the brain and in the spinal cord, showed statistically significant improvements at 12 months in every patient. While highly preliminary and involving only a very small number of patients, these results at least raise the possibility of a significant (though very partial) underlying repair effect within the damaged nervous system.
We believe this urgently requires further testing - both to accelerate benefit towards patients, and to begin improving therapeutic efficacy. We therefore propose a programme of MS BM stem cell research, including (1) a much larger ('phase two') controlled trial, treating 70 patients with longstanding MS; and (2) a parallel study of the mechanisms of action, studying and comparing BM cells from treated MS patients and control subjects, establishing which of the various cell types contribute to efficacy, and which specific repair mechanism(s) are important. Our trial has been funded by a grant from a USA foundation; this application seeks funding to carry out studies into how these cells work - and, importantly, whether there are differences between BM cells from MS patients and those from non-MS 'controls'. We hope these studies will not only confirm the therapeutic benefit of this approach, but also provide the basis for improving the magnitude and impact of this novel, exciting treatment.

Cell therapy offers new possibilities for reducing tissue damage, and progressive disability, in multiple sclerosis [MS]. We hypothesise that autologous bone marrow [BM] cell therapy in chronic MS offers durable benefit; and that the mechanisms are multiple, but include the reparative and/or neuroprotective effects of more than one BM cell sub-population. On a background of our own and others' experimental BM stem cell studies, we completed a Phase 1 trial of intravenous BM cell therapy in 6 patients with chronic MS (www.nature.com/clpt/journal/v87/n6/full/clpt201044a.html). Safety was confirmed, and intensive serial neurophysiological tests showed statistically significant improvements at 12 months in every patient. While uncontrolled and highly preliminary, these results are consistent with a beneficial effect within the damaged CNS.
We believe this urgently requires further testing - both to accelerate benefit towards patients, and to improve therapeutic efficacy. We therefore propose a programme of translational and clinical stem cell research, aiming (1) to continue translation with a Phase 2 controlled trial of autologous BM cells in 80 patients with chronic MS; and (2) in parallel to explore potential mechanisms of action by studying BM cells from recruited MS patients and non-MS controls, aiming to establish what the various BM sub-populations might contribute to efficacy; which reparative mechanism(s) might be important; whether monocytes contribute to the effect; and whether there are differences in therapeutic properties between BM cells from MS patients and those from non-MS controls.
Our trial has been funded by a grant from a USA foundation; this application seeks MRC funding to exploit the unique back-translational opportunity presented by the trial to explore how this therapy might work - and, potentially, provide the basis for improving the magnitude and impact of this treatment.

Who will benefit from this research?
We hope and believe that MS patients and carers, MS physicians, and neuroscientists interested in MS will benefit. We believe the benefit will be wider than this, and that patients, carers, neurologists and neuroscientists with a stake or interest in other neurodegenerative diseases will also benefit. This applies not just to individuals in the UK, but internationally.
How will they benefit from this research?
As mentioned elsewhere, our approach of using whole, filtered but unfractionated bone marrow cells in MS is not, to our knowledge, being actively pursued elsewhere in the UK or beyond, in MS (large trials in patients with coronary and peripheral vascular disease, and in other systemic disorders have been published, as have phase one studies in stroke and retinal degeneration). Our studies will help open or close this avenue, with obvious benefits to the research community, to clinicians and indeed to patients - and also to funding bodies - in either case.