Stem cell therapy for neuromuscular disorders
Neuromuscular disorders (NMDs) are a group ofdisorders primarily involving the motor units in muscle. Motor units arecomposed of a group of muscle fibers together with the nerve that causes thefibers to contract. NMDs are adiverse group of diseases, many of which have a genetic origin, that affect skeletal muscle and nerves that controlvoluntary muscles. When neurons areaffected, communication between the nervous system and the muscle breaks downand, as a result, the muscles weaken and deteriorate - leading to muscle lossand wasting.
Stem cell research has proven to be a promising toolin the development of novel therapies for NMDs. Stem cells are undifferentiatedand have the ability to self-renew and to form every cell type in the body as aresult of which they develop and maintain the body's tissues and organs. Stemcells are currently used for several forms of cell-based therapy, but are notyet accepted as part of routine medical practice for the treatment ofneurological disorders.
Although embryonic stem cells (ESC) are capable ofbecoming neural cells, the risk of tumours, as well as the ethicalcontroversies related to their origin, limits their use. Adult stem cells areparticularly attractive for cell-based therapy. They have several advantagesover ESCs but their ability to change into neural cells remains a matter ofdebate.
For autologous transplants stem cells are harvested from the body via minimally invasive procedures, and are then transplanted back into the same patient and the patient's immune system does not reject them. Although not common practice at present, the cells can be expanded in the laboratory. In genetic diseases, autologous stem cell treatment will not be possible as the patient's stem cells carry the genetic mutation responsible for the disease. The use of stem cells from a donor who does not carry the mutation- allogeneic transplantation - carries the risk that the patient's immune system will reject the transplanted cells unless an almost perfect match is found. In order to overcome rejection, the recipient's immune system is suppressed, but as can be expected, the side-effects associated with immuno suppressive therapy remain a major obstacle.
A number of pre-clinical and early clinical studies have indicated that stem cell therapy is safe and has the potential to be usedin the treatment of NMDs. A pilot study (Slavin) demonstrated that stem cell transplantation is safe and feasible following intrathecal and intravenous delivery in 12 patients suffering from neurological diseases including: amyotrophic lateral sclerosis (ALS), cerebral atrophy, motorneuron disease, progressive spinal palsy and multiple sclerosis. Apart from one patient who developed self-limited mild meningeal signs that disappeared after two days, no other side effects were observed within an observation period of more than a year.
In another study (Deda) 13 ALS patients were treated with bone marrow-derived stem cells and after a one year follow-up period, nine displayed clinical improvement. Work by the group of Mazzini also suggests thatbone marrow derived cells might be useful in ALS patients. The group has recently reported data from a Phase I clinical trial that confirmed that transplantation into the thoracic spinal cord of ALS patients is safe. Nostructural changes (including tumour formation) in either the brain or spinal cord were detected following treatment.
Although there is evidence that stem cell therapy canbe safely administered in NMDs and other neurological disorders, neuronalsubstitution appears to be an ambitious and complex outcome that has yet to berealised. Accumulating evidence from experimental studies suggests that thebenefit derived from adult-derived stem cell therapy in neurological disordersis not related to neuron replacement. Rather, benefits may be afforded bybiological activities attributed to the stem cells that interfere with themechanisms responsible for disease progression. Adult stem cells can respond tosignals produced by diseased tissues. Some stem cells can counter inflammatoryprocesses that are normally activated during disease. Adult stem cells can alsostimulate self-repair processes and have been associated with the increased growthof new blood vessels after transplantation.
The application of stem cells in neurological disorders is still in an early experimental phase and is as yet unproven from aclinical or therapeutic perspective. It seems likely that adult stem cells may promote neuroprotective and neuromodulatory effects and may therefore be considered for application in NMDs. Although there is pre-clinical and early clinical evidence which suggests that cell-based therapy may be beneficial, larger scale clinical trials will be necessary to demonstrate safety andefficacy in the use of stem cells for the treatment of NMDs. It will also be important to understand the mechanisms underlying the reported beneficial effects of stem cells in NMD patients.
- Marnie Potgieter, Michael S. Pepper
Department of Immunology, Faculty of Health Sciences, University of Pretoria