Healey Center, Mass General Hospital, Harvard Medical School, Boston, MA, USA.
Research and Development, Brainstorm Cell Therapeutics, New York, NY, USA.
Muscle Nerve. 2022 Mar;65(3):291-302. doi: 10.1002/mus.27472. Epub 2022 Jan 5.
INTRODUCTION/AIMS: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative illness with great unmet patient need. We aimed to evaluate whether mesenchymal stem cells induced to secrete high levels of neurotrophic factors (MSC-NTF), a novel autologous cell-therapy capable of targeting multiple pathways, could safely slow ALS disease progression.
This randomized, double-blind, placebo-controlled study enrolled ALS participants meeting revised El Escorial criteria, revised ALS Functional Rating Scale (ALSFRS-R) ≥25 (screening) and ≥3 ALSFRS-R points decline prior to randomization. Participants received three treatments of MSC-NTF or placebo intrathecally. The primary endpoint evaluated efficacy of MSC-NTF through a responder analysis and safety. A change in disease progression post-treatment of ≥1.25 points/mo defines a clinical response. A pre-specified analysis leveraged baseline ALSFRS-R of 35 as a subgroup threshold.
Overall, MSC-NTF treatment was well tolerated; there were no safety concerns. Thirty-three percent of MSC-NTF and 28% of placebo participants met clinical response criteria at 28 wk (odds ratio [OR] = 1.33, P = .45); thus, the primary endpoint was not met. A pre-specified analysis of participants with baseline ALSFRS-R ≥ 35 (n = 58) showed a clinical response rate at 28 wk of 35% MSC-NTF and 16% placebo (OR = 2.6, P = .29). Significant improvements in cerebrospinal biomarkers of neuroinflammation, neurodegeneration, and neurotrophic factor support were observed with MSC-NTF, with placebo unchanged.
The study did not reach statistical significance on the primary endpoint. However, a pre-specified subgroup suggests that MSC-NTF participants with less severe disease may have retained more function compared to placebo. Given the unmet patient need, the results of this trial warrant further investigation.
介绍/目的：肌萎缩侧索硬化症（ALS）是一种致命的神经退行性疾病，患者有巨大的未满足的需求。我们旨在评估是否可以使用间充质干细胞（MSC）诱导其分泌高水平的神经营养因子（MSC-NTF），这是一种新型的自体细胞疗法，能够靶向多种途径，安全地减缓 ALS 的疾病进展。
这项随机、双盲、安慰剂对照的研究纳入了符合修订后的埃斯克里尔标准的 ALS 参与者，他们的修订后的 ALS 功能评定量表（ALSFRS-R）评分≥25（筛选），且在随机分组前至少下降了 3 个 ALSFRS-R 评分。参与者接受三次鞘内注射 MSC-NTF 或安慰剂的治疗。主要终点通过应答者分析和安全性评估来评估 MSC-NTF 的疗效。治疗后疾病进展的变化≥1.25 分/月定义为临床反应。一项预先指定的分析利用基线 ALSFRS-R 为 35 作为亚组阈值。
总体而言，MSC-NTF 治疗耐受性良好，没有安全性问题。28 周时，33%的 MSC-NTF 组和 28%的安慰剂组符合临床反应标准（优势比[OR]为 1.33，P=0.45）；因此，主要终点未达到。对基线 ALSFRS-R≥35 的参与者（n=58）进行的预先指定分析显示，28 周时 MSC-NTF 组的临床反应率为 35%，安慰剂组为 16%（OR 为 2.6，P=0.29）。与安慰剂相比，MSC-NTF 治疗可显著改善神经炎症、神经退行性变和神经营养因子的脑脊液生物标志物。
该研究在主要终点上未达到统计学意义。然而，一个预先指定的亚组表明，与安慰剂相比，疾病程度较轻的 MSC-NTF 组可能保留了更多的功能。鉴于患者的未满足需求，该试验的结果值得进一步研究。
