Although effective immunotherapies exist which down-regulate the autoimmune anti-myelin reactivity and reduce the rate of relapses of multiple sclerosis (like Copaxone and interferons), there is no effective means today to stop the progression of disability and induce rebuilding of the destroyed myelin (re-myelination).
There is currently no permanent cure for multiple sclerosis, although there are several treatments available for ameliorating the symptoms and managing the neurological conditions as a result of the disease process.
Medical treatments currently are aimed at returning function after an attack and preventing disability rather than tackling the pathophysiological disease process.
Neuronal stem cells have been shown to possess the ability to restore neuronal activity and produce new neurons through transdifferentiation. Various other types of stem cells have been tested in animal models with promising results, revealing a potential for restoration of the neurological function in neuroimmune and neurodegenerative conditions and in central nervous system traumatic injury.
Adult bone marrow derived mesenchymal stromal cells (MSC) have been shown to induce similar (to the neuronal stem cells) immunomodulatory and neuroregenerative effects and were shown in our laboratory to induce neuroprotection in the animal model of chronic experimental autoimmune encephalomyelitis (EAE).
These bone marrow derived mesenchymal stromal cells offer practical advantages for clinical therapeutic applications, since they can be obtained from the adult bone marrow and therefore the patient can be the donor for himself, without any danger for rejection of the cells. In addition, mesenchymal stromal cells carry a safer profile and are less prone to malignant transformation.
Future medical therapies need to effect mechanisms that will aid the remyelinating of chronically demyelinated axons. Two distinct approaches should be evaluated in order to promote myelin repair; firstly the endogenous myelin repair processes may be stimulated through the delivery of growth factors, and secondly the repair process could be augmented through the delivery of exogenous stem cells with potential for myelination and regeneration.
Effective treatment for multiple sclerosis also requires modulation of the immune system, since demyelination is associated with specific immunological activation and chronic auto immune inflammatory response.
Karussis and Kassis described how different stem cells migrated to areas within white matter lesions (plaques) and possess the ability to support the regrowth of neurons and regeneration of the affected myelin. This is postulated to occur through both the endogenous resident CNS stem cells regenerating and by differentiation of the transplanted stem cells into neurons and myelin-producing oligodendrocytes. These stem cells also possess immunomodulating properties which are crucial if treatment for multiple sclerosis is to halt the auto immune inflammatory process.
Several types of stem cells have the capacity for promoting myelin repair, as well as modulating the immune response; stem cells are therefore potential candidates for the successful treatment of multiple sclerosis. With inflammatory diseases which are diffuse and widespread such as multiple sclerosis, intravenous injection of stem cells can be used and has been demonstrated as an appropriate means of diffuse delivery of stem cells.
Many different stem cell types, including neural stem cells and precursors, have been postulated for therapy. There are however complexities in obtaining neural stem cells from the adult CNS; this obviously does not pose a problem for embryonic stem cells. A group from the University of California, San Francisco, published their findings in The Scientist (July 2007) cautioning against the notion that neural stem cells can regenerate into any type of neuron.
This group has revealed that it is possible for scientists to manipulate neural stem cells in vitro to make them more flexible, hence more likely to regenerate into the type of neural cell that one is trying to repair. Our team will only utilise neural stem cells that have already shown the ability in vitro to regenerate into glial cells and thus will remyelinate the damaged axons once injected into patients.
Almost ten years ago adult bone marrow cells were shown to have the ability to differentiate to oligodendroglial cells, indicating their suitability for treating demyelinating diseases. At the same time, a phase II trial utilising autologous bone marrow stem cell transplantation to treat 85 patients for progressive multiple sclerosis was conducted in 20 European centres. Neurological improvement was recorded in 21% of patients; confirmed progression-free survival was documented in 74% of patients at 3 years; disease progression was reduced to only 20%.
Additionally, it was reported that autologous haematopoietic stem cell transplantation treatments could regenerate a tolerant immune system and become a potentially effective rescue therapy for the subset of patients with aggressive forms of multiple sclerosis, refractory to existing immunomodulatory and immunosuppressive agents. Cassiani-Ingoni and fellow investigators, suggest that bone marrow stem cell transplantation can suppress the autoimmune inflammatory disease in the majority of multiple sclerosis patients, but is able to retard the clinical progression only in patients who were treated during the early stages of the disease.
(Mesenchymal stem cells are non-haematopoietic stem cells derived from marrow or umbilical cord). Evidence supports that mesenchymal stem cells have the ability to generate cells with the characteristics of neurons and glial cells and consequently promote repair within the injured CNS. How mesenchymal stem cells lead to functional recovery in the damaged adult CNS is not clearly determined. It is postulated that transplanted multipotent cells migrate to the injury sites, proliferate, and then differentiate into the appropriate neural cells, which then leads to neural repair and regeneration.
Although mesenchymal stem cells possess high survival and migration potential, the proportion that may be directed towards neural differentiation appears to be relatively small. Mesenchymal stem cells, perhaps via the release of soluble neurochemical signals at the origin of neural damage, exert a direct influence on the endogenous neural stem cells to promote repair through neuro- and oligodendrogenesis.
Mesenchymal stem cells also exert immunomodulatory effects through inducing suppression of the autoimmune myelin-targeting lymphocytes. Mesenchymal stem cells can be harvested from the bone marrow of the patient, thereby reducing the risk for developing reactions.
CD34+ stem cells are multipotent haematopoietic stem cells found in bone marrow and umbilical cord. These stem cells are capable of transforming into neuroprotective glial and myelin-producing oligodendrocytes (10). A proposed advantage of umbilical cord CD34+ stem cell transplantation is that, when administered, virtually no side effects are evident (10).
There are numerous anecdotal results for treatment of multiple sclerosis with stem cells. Many of the anecdotal reports reveal remarkable benefit from stem cell treatment for the disease. Since this condition does fluctuate many critics are not convinced that these benefits are derived from stem cell treatment.
To date there have been no ‘gold standard’ randomised double blind placebo controlled trials. Many stem cell treatments are performed in small clinics where the results are not documented and validated, or are from completely unregulated clinics in third world countries.
See References (below) for other trials into treatment with stem cells for multiple sclerosis.
Significant advances are being made daily in researching the therapeutic potential of stem cells for neurodegenerative diseases. There are already several facilities offering stem cell treatments but before proceeding with any treatment please discuss this with your treating neurologist or our stem cell experts.
Transplanting stem cells into focal multiple sclerosis lesions will be the ultimate therapeutic approach, although this will involve a neurosurgical procedure. Clinical trials are needed to determine whether exogenous stem cells are able to survive, differentiate and myelinate axons in plaques. If you would like to be considered for a clinical trial please contact our research trials coordinator.
Multiple sclerosis is a multifocal inflammatory disease of the central nervous system, which affects young individuals and causes paralysis of the limbs, sensation, visual and sphincter problems. The estimated incidence is 1 in 1000 in the US and Europe. It is also more prevalent in colder climates and has become the commonest neurodegenerative disease as its incidence is rising.
The disease is caused by an autoimmune mechanism, i.e. the immune system produces antibodies and cells which attack the self myelin antigens, thereby causing demyelination. Demyelination occurs via a process of gradual destruction of the myelin sheath, which surrounds the axons (neural network) of nerve cells (neurons), leading to axonal injury and consequently severely impaired nerve conduction with its neurological conditions as a result of the disease process.
The disease derives its name from the multiple scleroses (scars or plaques) that are created on the myelinated axons. This damage occurs in patches that appear as distinct lesions at MRI. Recurrent episodes of demyelination eventually deteriorate the myelin sheath with repeated remyelinations causing scarring and deterioration of the functioning of the axons. Regeneration of the myelin sheath occurs via remyelination of the axons mediated through cells known as oligodendrocytes and oligo-dendritic stem cells. This only takes place in the early phases of the disease but electron micrographic evidence has revealed that the regenerated myelin sheaths are thinner and less effective at nerve conduction.
The disease is clinically evident with relapses of neurological disability due to the dysfunction of the areas (plaques of multiple sclerosis) in which damage of myelin occurs. Disability can accumulate with time and the disease enters a progressive phase due to damage of the axons and irreversible neurodegeneration. This is why treatment for multiple sclerosis has to be instigated as early as possible to prevent permanent damage of the neurons, which is very difficult to treat.
With progression of the disease the central nervous system becomes unable to recruit oligodendrocyte stem cells, but it is unclear why this appears to be inhibited with longstanding disease. Perhaps it is due to secondary auto immune inflammatory responses. Once again the benefits of treatment are obviously greater the sooner the treatment is initiated.
Multiple sclerosis causes a myriad of symptoms depending on where in the central nervous system the lesions occur. Neurological deficits inexorably and progressively accumulate causing worsening of the clinical picture. Unfortunately there are numerous complicating factors resulting in the unpredictable course of the disease. This makes it very difficult to give prognosticators of disease progression. There are periods of dormant activity followed by periods of unpredictable exacerbations, during which there is steady progression of the disease process with the resultant decline in neurological function, eventually leading to intractable neurological disability.
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