Neurology Department, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
BrainStorm Cell Therapeutics, Petach Tikva, Israel.
JAMA Neurol. 2016 Mar;73(3):337-44. doi: 10.1001/jamaneurol.2015.4321.
Preclinical studies have shown that neurotrophic growth factors (NTFs) extend the survival of motor neurons in amyotrophic lateral sclerosis (ALS) and that the combined delivery of these neurotrophic factors has a strong synergistic effect. We have developed a culture-based method for inducing mesenchymal stem cells (MSCs) to secrete neurotrophic factors. These MSC-NTF cells have been shown to be protective in several animal models of neurodegenerative diseases.
To determine the safety and possible clinical efficacy of autologous MSC-NTF cells transplantation in patients with ALS.
DESIGN, SETTING, AND PARTICIPANTS: In these open-label proof-of-concept studies, patients with ALS were enrolled between June 2011 and October 2014 at the Hadassah Medical Center in Jerusalem, Israel. All patients were followed up for 3 months before transplantation and 6 months after transplantation. In the phase 1/2 part of the trial, 6 patients with early-stage ALS were injected intramuscularly (IM) and 6 patients with more advanced disease were transplanted intrathecally (IT). In the second stage, a phase 2a dose-escalating study, 14 patients with early-stage ALS received a combined IM and IT transplantation of autologous MSC-NTF cells.
Patients were administered a single dose of MSC-NTF cells.
The primary end points of the studies were safety and tolerability of this cell therapy. Secondary end points included the effects of the treatment on various clinical parameters, such as the ALS Functional Rating Scale-Revised score and the respiratory function.
Among the 12 patients in the phase 1/2 trial and the 14 patients in the phase 2a trial aged 20 and 75 years, the treatment was found to be safe and well tolerated over the study follow-up period. Most of the adverse effects were mild and transient, not including any treatment-related serious adverse event. The rate of progression of the forced vital capacity and of the ALS Functional Rating Scale-Revised score in the IT (or IT+IM)-treated patients was reduced (from -5.1% to -1.2%/month percentage predicted forced vital capacity, P < .04 and from -1.2 to 0.6 ALS Functional Rating Scale-Revised points/month, P = .052) during the 6 months following MSC-NTF cell transplantation vs the pretreatment period. Of these patients, 13 (87%) were defined as responders to either ALS Functional Rating Scale-Revised or forced vital capacity, having at least 25% improvement at 6 months after treatment in the slope of progression.
The results suggest that IT and IM administration of MSC-NTF cells in patients with ALS is safe and provide indications of possible clinical benefits, to be confirmed in upcoming clinical trials.
clinicaltrials.gov Identifiers: NCT01051882 and NCT01777646.
重要性：临床前研究表明神经营养因子（NTFs）可延长肌萎缩侧索硬化症（ALS）中运动神经元的存活，并且这些神经营养因子的联合给药具有很强的协同作用。我们已经开发出一种基于培养的方法来诱导间充质干细胞（MSCs）分泌神经营养因子。这些 MSC-NTF 细胞已在几种神经退行性疾病的动物模型中显示出保护作用。
目的：确定自体 MSC-NTF 细胞移植在 ALS 患者中的安全性和可能的临床疗效。
设计、地点和参与者：在这些开放标签的概念验证研究中，以色列耶路撒冷哈达萨医疗中心于 2011 年 6 月至 2014 年 10 月间招募了 ALS 患者。所有患者在移植前 3 个月和移植后 6 个月进行随访。在试验的第 1/2 部分中，6 例早期 ALS 患者接受肌肉内（IM）注射，6 例晚期疾病患者接受鞘内（IT）移植。在第二阶段，一项 2a 期剂量递增研究中，14 例早期 ALS 患者接受了自体 MSC-NTF 细胞的 IM 和 IT 联合移植。
干预措施：患者接受单次 MSC-NTF 细胞剂量治疗。
主要结果和测量：研究的主要终点是该细胞疗法的安全性和耐受性。次要终点包括治疗对各种临床参数的影响，如 ALS 功能评定量表修订版评分和呼吸功能。
结果：在第 1/2 阶段试验的 12 例患者和第 2a 阶段试验的 14 例年龄在 20 岁至 75 岁的患者中，治疗在研究随访期间被发现是安全且耐受良好的。大多数不良事件为轻度和短暂，不包括任何与治疗相关的严重不良事件。在接受 IT（或 IT+IM）治疗的患者中，用力肺活量和 ALS 功能评定量表修订版评分的进展率降低（从预计用力肺活量的-5.1%降至-1.2%/月，P <.04 和从-1.2 到 0.6 ALS 功能评定量表修订版点/月，P =.052）在 MSC-NTF 细胞移植后的 6 个月内与预处理期相比。在这些患者中，13 名（87%）患者被定义为 ALS 功能评定量表修订版或用力肺活量的应答者，在治疗后 6 个月时斜率进展至少有 25%的改善。
结论和相关性：结果表明，在 ALS 患者中，IT 和 IM 给予 MSC-NTF 细胞是安全的，并提供了可能的临床益处的迹象，这将在即将进行的临床试验中得到证实。
试验注册：clinicaltrials.gov 标识符：NCT01051882 和 NCT01777646。
