Abstract
Background This study is aimed at investigating the safety and tolerability of the intra-arterial administration of autologous bone marrow-derived mesenchymal stem cells (BM-MSCs) in patients with multiple system atrophy- (MSA-) cerebellar type (MSA-C). Methods This was a single-center, open-label phase I clinical trial in patients with MSA-C. A three-stage dose escalation scheme (low-dose, 3.0 × 105 cells/kg; medium-dose, 6.0 × 105 cells/kg; high-dose, 9.0 × 105 cells/kg) was applied to determine the maximum tolerated dose of intra-arterial administration of BM-MSCs based on the no-observed-adverse-effect level derived from the toxicity study. The occurrence of adverse events was evaluated 1 day before and 1, 14, and 28 days after BM-MSC therapy. Additionally, we assessed changes in the Unified MSA Rating Scale (UMSARS) score 3 months after BM-MSC treatment. Results One serious adverse drug reaction (ADR) of leptomeningeal enhancement following the intra-arterial BM-MSC administration occurred in one patient in the low-dose group. The safety review of the Internal Monitoring Committee interpreted this as radiological evidence of the blood-brain barrier permeability for MSCs. No other ADRs were observed in the medium- or high-dose groups. In particular, no ischemic lesions on diffusion-weighted images were observed in any of the study participants. Additionally, the medium- and high-dose groups tended to show a slower increase in UMSARS scores than the low-dose group during the 3-month follow-up. Conclusion The present study confirmed that a single intra-arterial administration of autologous BM-MSCs is a safe and promising neuroprotective strategy in patients with MSA-C.
Highlights
Multiple system atrophy (MSA) is a sporadic neurodegenerative disorder that presents rapid disease progression and fatal prognosis
A three-stage dose escalation scheme was applied to determine the maximum tolerated dose of bone marrow-derived mesenchymal stem cells (BM-mesenchymal stem cells (MSCs)) based on the no-observed-adverse-effect level (NOAEL) derived from the toxicity study: the low-dose group (n = 3) received a single dose of 3:0 × 105 cells/kg, the medium-dose group (n = 3) received a single dose of 6:0 × 105 cells/kg, and the high-dose group (n = 3) received a single dose of 9:0 × 105 cells/kg, which was the highest dose for which we wanted to confirm safety based on our preclinical data (Supplementary Methods)
Nine patients (5 men and 4 women) who had been diagnosed with multiple system atrophy- (MSA-)C
Summary
Multiple system atrophy (MSA) is a sporadic neurodegenerative disorder that presents rapid disease progression and fatal prognosis. The pathogenesis of MSA is not yet fully understood, some pathways have been proposed, including axonal degeneration with α-synuclein deposition, mitochondrial dysfunction, microgliosis, and oxidative stress [3]. This study is aimed at investigating the safety and tolerability of the intra-arterial administration of autologous bone marrow-derived mesenchymal stem cells (BM-MSCs) in patients with multiple system atrophy- (MSA-) cerebellar type (MSA-C). A three-stage dose escalation scheme (low-dose, 3:0 × 105 cells/kg; medium-dose, 6:0 × 105 cells/kg; high-dose, 9:0 × 105 cells/kg) was applied to determine the maximum tolerated dose of intra-arterial administration of BM-MSCs based on the no-observed-adverse-effect level derived from the toxicity study. The present study confirmed that a single intra-arterial administration of autologous BM-MSCs is a safe and promising neuroprotective strategy in patients with MSA-C
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