Chung Seok Jong, Lee Tae Yong, Lee Yang Hyun, Baik KyoungWon, Jung Jin Ho, Yoo Han Soo, Shim Chang Jae, Eom Hyojin, Hong Ji-Yeon, Kim Dong Joon, Sohn Young H, Lee Phil Hyu
Department of Neurology, Yonsei University College of Medicine, Seoul 03722, Republic of Korea.
Department of Neurology, Yongin Severance Hospital, Yonsei University Health System, Yongin 16995, Republic of Korea.
Stem Cells Int. 2021 Oct 19;2021:9886877. doi: 10.1155/2021/9886877. eCollection 2021.
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).
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 × 10 cells/kg; medium-dose, 6.0 × 10 cells/kg; high-dose, 9.0 × 10 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.
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.
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.
本研究旨在调查自体骨髓间充质干细胞（BM-MSCs）动脉内给药治疗多系统萎缩小脑型（MSA-C）患者的安全性和耐受性。
这是一项针对MSA-C患者的单中心、开放标签的I期临床试验。采用三阶段剂量递增方案（低剂量，3.0×10⁶细胞/kg；中剂量，6.0×10⁶细胞/kg；高剂量，9.0×10⁶细胞/kg），根据毒性研究得出的未观察到不良反应水平来确定BM-MSCs动脉内给药的最大耐受剂量。在BM-MSC治疗前1天以及治疗后1天、14天和28天评估不良事件的发生情况。此外，我们在BM-MSC治疗3个月后评估统一MSA评定量表（UMSARS）评分的变化。
低剂量组有1例患者在动脉内注射BM-MSCs后发生了1例严重药物不良反应（ADR），表现为软脑膜强化。内部监测委员会的安全性审查将此解释为MSCs血脑屏障通透性的影像学证据。中剂量组和高剂量组未观察到其他ADR。特别是，在任何研究参与者中均未在扩散加权图像上观察到缺血性病变。此外，在3个月的随访期间，中剂量组和高剂量组的UMSARS评分升高趋势比低剂量组更缓慢。
本研究证实，单次自体BM-MSCs动脉内给药对MSA-C患者是一种安全且有前景的神经保护策略。
