Intrathecal Administration of Autologous Mesenchymal Stem Cells in Multiple System Atrophy – A Phase I/II Dose-Escalation Trial (S11.002)

Objective: To explore intrathecal administration of autologous mesenchymal stem cells (MSCs) as therapeutic approach to multiple system atrophy (MSA). Background: MSA is a rapidly progressive neurodegenerative disease for which there is no proven disease-modifying treatment. Recent insights into pathophysiologic mechanisms suggest a critical role of deprivation of neurotrophic factors which have been shown to be secreted by MSCs. Design/Methods: Utilizing a dose-escalation design we delivered adipose-derived autologous MSCs intrathecally via lumbar puncture to patients with early MSA. Between 10 and 200 million MSCs were administered in three predefined dose tiers and patients were closely followed for one year with serial clinical, laboratory, and MRI surveillance. Primary endpoints were frequency and type of adverse events; secondary endpoints were the rate of disease progression assessed by the Unified MSA Rating Scale (UMSARS) and indices of autonomic function. A Bayesian approach utilizing the placebo group of our recently completed Rifampicin treatment trial allowed for assessment of potential efficacy. Results: 24 patients were enrolled. There were no attributable serious adverse events and the procedure was generally well tolerated. At the highest dose tier, 3 of 4 patients developed low back/thigh pain, associated with thickening/enhancement of lumbar nerve roots and variable elevation of CSF protein and cell count. Although there were no associated neurologic deficits, we decided that dose-limiting toxicity was reached. 5 of 12 patients in the medium dose-tier developed similar, but milder and transient discomfort. Rate of progression (UMSARS Total) was markedly lower compared to the placebo group (0.43±0.59 versus 1.22±1.30 points/month, p=0.009); this difference was more pronounced for the medium than the low dose-tier. Conclusions: Intrathecal MSC administration in MSA is safe and well tolerated but can be associated with a painful “implantation response” at high doses. The apparent dose-dependent slowing of disease progression is highly intriguing and the basis for a planned placebo-controlled phase II/III study. Study Supported by: Supported by NIH (P01NS44233, U54NS065736, K23NS075141, R01FD004789, R01NS092625, UL1TR000135), Cure MSA Foundation, and Mayo Funds. Disclosure: Dr. Singer has nothing to disclose. Dr. Dietz has nothing to disclose. Dr. Zeller has nothing to disclose. Dr. Gehrking has nothing to disclose. Dr. Schmelzer has nothing to disclose. Dr. Sletten has nothing to disclose. Dr. Gehrking has nothing to disclose. Dr. Coon has nothing to disclose. Dr. Sandroni has nothing to disclose. Dr. Benarroch has received personal compensation in an editorial capacity for being a section editor for Neurology. Dr. Fealey has nothing to disclose. Dr. Matsumoto has nothing to disclose. Dr. Bower has nothing to disclose. Dr. Ahlskog has nothing to disclose. Dr. Hassan has nothing to disclose. Dr. McKeon has received research support from MedImmune and Euroimmun. Dr. Klassen has nothing to disclose. Dr. Low has received personal compensation for activities with Chelsea Therapeutics, Pfizer Inc., and WR Medical Electronics Company as a consultant.