SAN ANTONIO—Stem cell therapy for multiple sclerosis (MS) is “on the threshold of clinical translation,” Neil Scolding, PhD, reported at the 24th Annual Meeting of the Consortium of MS Centers. “Our increasing knowledge of stem cells—bone marrow stem cells in particular—has emerged [during the past decade] in parallel with our increasing knowledge of MS.” Dr. Scolding is a Professor of Neurology at the Institute of Clinical Neuroscience, University of Bristol, United Kingdom.
“MS appears to be a disease that is particularly amenable for reparative therapy,” he said. “We’ve known for quite a while that bone marrow–derived stem cells, and adult stem cells in general, are able to achieve reparative effects by calling on a number of different functions…. [They] can stimulate or reprogram repair both directly and through a range of other noncanonical mechanisms, including fusion, immune modulation, neuroprotection, growth factor production, reduced scar formation, effects on local repair and other cells, and transdifferentiation.”
In particular, mesenchymal stem cells (MSC)—nonhaematopoietic stem cells derived from bone marrow, skin, and adipose tissue—appear very promising for the future of MS therapy, he said. Their potential immunomodulatory and reparative properties are being investigated in a number of centers worldwide.
Although the precise mechanism of immunomodulation in MSCs is not clearly understood, research indicates that these cells suppress T- and B-cell functions and natural killer cells. Studies in experimental autoimmune encephalomyelitis (EAE) mice showed decreased inflammatory infiltrates in the CNS and a reduction in demyelination after MSC transplantation.
Using MSCs in EAE mice, Dr. Scolding’s and other research teams have found that tissue damage was reduced, with a very pronounced effect on the suppression of EAE, with “evidence suggesting both a peripheral and a central role for these cells,” he explained.
Research has shown that oligodentrocyte progenitor cells—endogenous neural precursors capable of generating more myelin—exist within lesions. “We know [there is] a certain amount of spontaneous myelin repair already occurring in MS, … [which] means that any cell therapy needs to enhance something that is happening already rather than starting from scratch,” Dr. Scolding noted.
Precisely how MSCs reverse myelin damage is unclear. Initial evidence suggested that MSCs could turn into oligodendrocytes. “It’s certainly true that these cells express antigens that we associate with neuronal or glial markers, such as nestin, βIII-tubulin, GFAP, and the oligodendrocyte marker 04. And it is possible to manipulate the cell populations to increase the proportions expressing those antigens,” Dr. Scolding said. “But what we haven’t been able to show is any suggestion that these cells might turn into process-bearing oligodendrocytes that are functionally capable of making myelin.” He added that the current “consensus is that maybe the MSCs themselves may not be able to make oligodendrocytes,” but rather have an indirect effect on the endogenous repair processes.
“Whatever the mechanism is, it is quite clear that bone marrow cells injected intravenously can promote remyelination,” he said, adding he believes it is due to a “myelin promoting effect and not just a direct consequence of immune processes suppressing inflammation.”
In addition to their anti-inflammatory properties, MSCs possess the apparent ability to home in on lesions, migrating toward chemokines expressed in the lesions. “These cells are capable of finding their way to inflammation [and are] apparently attracted to damaged tissue,” Dr. Scolding reported.
“These cells have powerful neuroprotective properties,” he added, pointing to research showing that bone marrow stromal cells reduce axonal loss in EAE mice. In addition, investigators found MSCs secrete brain-derived neurotrophic factor and superoxide dismutase, both of which can promote neuronal survival. In addition, he noted, circulating bone marrow stem cells enter the brain and spinal cord and may contribute to the repair of damaged tissue.
Another attractive aspect of MSC therapy is the potential to use a patient’s own bone marrow. In the May 5 online Clinical Pharmacology and Therapeutics, Dr. Scolding and colleagues published results of the phase I Study of Intravenous Autologous Marrow in Multiple Sclerosis (SIAMMS) assessing the safety and feasibility of IV autologous bone marrow cell therapy without immunosuppressive preconditioning.
During the 12-month study of six subjects with relapsing-progressive MS, subjects’ clinical disability scores either improved or had no change. Electrophysiologic tests, however, showed statistically significant improvements in all patients. The treatment was well-tolerated by subjects and not associated with any serious side effects.
“The lack of serious adverse effects and the suggestion of a beneficial effect in this small sample of patients with progressive disease justify conducting a larger phase II/III study to make a fuller assessment of the efficacy of mobilization of autologous bone marrow in patients with MS,” Dr. Scolding and colleagues concluded.