Mesenchymal Stem Cells Therapy for Multiple System Atrophy

Abstract & Commentary

By Alexander Shtilbans, MD, PhD, Assistant Professor of Neurology, Weill Cornell Medical College. Dr. Shtilbans reports no financial relationships relevant to this field of study.

Synopsis: Mesenchymal stem cells for the treatment of multiple system atrophy is a promising potential therapy, but requires further investigation regarding both safety and efficacy.

Source: Lee PH, et al. A randomized trial of mesenchymal stem cells in multiple system atrophy. Ann Neurol 2012;72:32-40.

Multiple system atrophy (MSA) is a neurodegenerative disorder potentially resulting in pyramidal, extrapyramidal, cerebellar, and autonomic dysfunction. It is associated with deposition of cytoplasmic α-synuclein protein aggregates and loss of surrounding neurons in the brainstem, cerebellum, and basal ganglia. The course of the illness is more rapid than Parkinson's disease, averaging in 7-10 years disease duration. There is no cure and most of the cases do not respond to dopaminergic therapies. A 2008 open-label study by Lee et al has shown that autologous mesenchymal stem cell (MSC) injections could delay progression of neurological symptoms in MSA-C (cerebellar type), although the lack of blinding brought some criticism.1 In the current study, the authors conducted a randomized, double-blind, placebo-controlled trial aimed at detecting a change in severity of neurological deficits in active and placebo groups, evaluated by total unified MSA rating scale (UMSARS) over a 360-day period. The second endpoint was a change in part II (motor) of UMSARS, cerebral glucose metabolism, gray matter density, and cognitive performance. The authors recruited 33 patients with probable MSA-C and randomized them to the active and placebo groups. Fourteen patients received intra-arterial and intravenous mesenchymal stem cell injections and 17 patients received placebo in similar fashion. Of the 14 patients in the active arm of the study, 11 completed the trial, whereas 16 patients from the placebo group completed the trial. The most common side effects associated with the infusions were acute cerebral ischemic lesions seen on DWI MRI sequences performed immediately after the intra-arterial infusions. Those lesions were seen in 29% of the MSC treated patients and in 35% of placebo patients. Clinical assessments were performed at baseline and at 30, 60, 90, 120, 150, 180, 240, 300, and 360 days after the initial injection. The patients who received stem cell therapy showed a statistically significant smaller increase in the total and part II UMSARS scores compared to the placebo group. There was no statistically significant difference in the UMSARS part I addressing quality of life. FDG PET scans showed a smaller decrease in glucose metabolism in the cerebellum of the patients in the active group of the trial. The stem cell group also had more preservation of the gray matter density during the follow-up period than the placebo group. Neuropsychological evaluation showed that the stem cell group had no significant deterioration of cognitive performance compared to worsening cognitive functions in the placebo group. The post-hoc analysis showed the most significant difference in the total UMSARS score between the MSC and placebo groups on day 240.


MSC therapy has been studied and found to be beneficial in animal and laboratory models of several neurodegenerative diseases including amyotrophic lateral sclerosis, Parkinson's disease, Friedreich's ataxia, and Huntington disease. The exact mechanism of action of MSC in neurodegeneration is not known, but it is proposed to possibly modulate neuroinflammatory and apoptotic processes, decrease glutamate excitotoxicity, or improve deficiency of various growth factors. The delivery of MSC to the brain might be compromised by the blood brain barrier. However, this barrier might be less intact in the multiple system atrophy than in normal subjects. The authors chose both intra-arterial and intravenous routes for infusions of the MSC, although the latter is more inferior because of entrapment of the stem cells in solid organs. The intra-arterial infusion in turn may result in ischemic lesions in the brain as evidenced by the adverse effects profile observed in the study. Overall, the investigators met their primary endpoint of a statistically significant difference in the UMSARS scores, along with observed positive results in secondary endpoints such as glucose metabolism, cortical density, and cognitive scores. The authors recognized the limitations of this study, which include the relatively small number of subjects, only mild and moderate stages of the disease, and inclusion of only MSA-C patients. Moreover, the safety of intra-arterial infusions is of concern given the significant percentage of patients developing ischemic lesions seen on the MRI, even though they are likely asymptomatic. The most significant difference in the treatment effect was observed at day 240, after which the patients who received stem cell treatment seemed to have worsened at a slightly higher rate than placebo patients, but retained some improvement in the UMSARS scores at the end of the study (360 days). This might present a need for repeated infusions which in turn could result in accumulative ischemic burden to the patients, thus presenting unacceptable risk. However, the study did demonstrate evidence of a possible neuroprotective effect of the mesenchymal stem cells. Therefore, a repeat multicenter trial with patients of all types of multiple system atrophy would be warranted when the safety concerns of the MSC delivery system are addressed.


1. Lee PH, et al. Autologous mesenchymal stem cell therapy delays the progression of neurological deficits in patients with multiple system atrophy. Clin Pharmacol Ther 2008;83:723-730.