Intrathecal Mesenchymal Stem Cells in Progressive Multiple Sclerosis: A Randomized, Double-Blind, Placebo-Controlled Trial (SMART-MS)

BACKGROUND AND OBJECTIVES: There is an unmet need for neuroregenerative therapies in multiple sclerosis (MS). Mesenchymal stem cells (MSCs) have shown immunomodulatory and regenerative effects in preclinical models and early clinical studies. Intrathecal administration may enhance therapeutic potential by direct delivery to the CNS. However, randomized, placebo-controlled trials are needed to establish safety and efficacy. The objective of this trial was to assess whether a single intrathecal administration of autologous MSCs could provide evidence of a neuroregenerative effect in progressive MS. METHODS: In this randomized, double-blind, placebo-controlled phase I/II trial (NCT04749667), patients with progressive MS enrolled at 4 Norwegian tertiary hospitals received a single intrathecal injection of autologous bone marrow-derived MSCs (1 × 106 cells/kg) in a crossover design. The primary end point was the change in latency of combined evoked potentials at 6 months. Secondary end points included safety, brain MRI measures, functional and ophthalmologic assessments, and serum biomarkers at 6 and 12 months. Exploratory analyses comprised proteomic profiling of CSF. Outcomes were analyzed using baseline-adjusted regression models. RESULTS: A total of 18 patients were included (mean age 46.7 years; 55.6% female). No significant between-group difference was observed for the primary end point (β = -0.31, 95% CI -1.84 to 1.22, p = 0.668). At 6 months, patients in the MSC group showed reduced cerebral atrophy on MRI (β = 9.37, 95% CI 0.29 to 18.45, p = 0.044) and lower serum glial fibrillary acidic protein levels (β = -16.3 pg/mL, 95% CI -33.0 to 0.3, p = 0.054), but neither were sustained at 12 months. Exploratory CSF proteomics revealed reductions in multiple inflammation-related proteins at 6 months. One serious adverse event was deemed probably related to MSC treatment. Common adverse events included fever (n = 9) and low back pain (n = 10) after MSC administration, and spinal MRI abnormalities with fluid loculations and nerve root clumping (n = 7) at 6 months. One patient developed chronic coccygeal pain attributed to arachnoiditis. DISCUSSION: A neuroregenerative effect was not detected, although interpretation may be limited by the small sample size. Adverse events suggest an acute localized inflammatory reaction after MSC administration. Our findings suggest that intrathecal administration of MSCs in progressive MS should be approached with caution in future studies. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that, in patients with progressive multiple sclerosis, treatment with a single intrathecal administration of autologous mesenchymal stem cells does not provide neuroregenerative effect, as assessed by a composite evoked potential score. TRIAL REGISTRATION: ClinicalTrials.gov (NCT04749667); registered February 8, 2021; first patient enrolled August 9, 2021.