Amyotrophic Lateral Sclerosis Center, Neurology Unit, Department of Translational Medicine, University of Eastern Piedmont, Novara, Italy.
Department of Public Health and Pediatrics, University of Turin, Torino, Italy; Stem Cell Transplantation and Cellular Therapy Laboratory, Pediatric Onco-Hematology Division, Regina Margherita Children's Hospital, City of Health and Science of Turin, Torino, Italy.
Cytotherapy. 2023 Aug;25(8):798-802. doi: 10.1016/j.jcyt.2023.02.005. Epub 2023 Mar 15.
Thanks to their immunomodulatory, tissue-protective and regenerative properties, mesenchymal stromal cells (MSCs) are a promising approach for amyotrophic lateral sclerosis (ALS); however, trials are limited and few follow-up studies have been published. This post-hoc analysis aims to describe the potential long-term effects of MSCs in ALS, analyzing data from two phase 1 clinical trials in ALS patients conducted by our group in 2002 and 2006.
We conducted two consecutive phase 1 prospective, open, pilot clinical trials, enrolling a total of 19 ALS patients. We followed patients for the duration of the disease. For each patient, we used the European Network to Cure ALS (ENCALS) survival prediction model to retrospectively calculate the expected survival at diagnosis. We then compared the predicted disease duration with the observed survival, analyzing patients at a single-patient level.
Using the ENCALS model, we predicted short survival in one patient, intermediate survival in three patients, long survival in three patients and very long survival in 12 patients. The difference between predicted and observed survival for the whole group was significant and demonstrated a mean predicted survival of 70.79 months (standard deviation [SD], 27.53) and a mean observed survival of 118.8 months (SD, 89.26) (P = 0.016). Based on the monthly ALS Functional Rating Scale-Revised progression rate (median, 0.64/month), we considered 10 of 19 patients slow progressors and nine of 19 patients fast progressors. Of the slow progressors, eight of 10 (80%) had significantly increased disease duration compared with predicted, and only two (20%) had decreased estimated disease duration. By contrast, five of nine (55%) fast progressors had increased disease duration, whereas four (45%) had decreased disease duration. To date, four patients are still alive.
The current study represents the first very long-term analysis of survival as an effect of MSC focal transplantation in the central nervous system of ALS patients, demonstrating that MSC transplantation could potentially slow down ALS progression and improve survival. Due to the interindividual variability in clinical course, at the current state of our knowledge, we cannot generalize the results, but these data provide new insights for planning the next generation of efficacy MSC clinical trials in ALS.
间充质基质细胞（MSCs）具有免疫调节、组织保护和再生特性，是肌萎缩侧索硬化症（ALS）有希望的治疗方法；然而，试验有限，并且很少有随访研究发表。本事后分析旨在描述 MSCs 在 ALS 中的潜在长期疗效，分析我们小组在 2002 年和 2006 年进行的两项针对 ALS 患者的 1 期临床试验的数据。
我们进行了两项连续的 1 期前瞻性、开放性、试验性临床试验，共纳入 19 名 ALS 患者。我们对患者进行了疾病持续时间的随访。对于每个患者，我们使用欧洲肌萎缩侧索硬化症治疗网络（ENCALS）生存预测模型来回顾性计算诊断时的预期生存。然后，我们比较了预测的疾病持续时间和观察到的生存，对单个患者进行分析。
使用 ENCALS 模型，我们预测了一名患者的短期生存、三名患者的中期生存、三名患者的长期生存和 12 名患者的超长生存。整个组的预测生存与观察生存之间的差异具有统计学意义，表明平均预测生存为 70.79 个月（标准差 [SD]，27.53），平均观察生存为 118.8 个月（SD，89.26）（P=0.016）。基于每月肌萎缩侧索硬化功能评定量表修订后进展率（中位数，0.64/月），我们将 19 名患者中的 10 名视为缓慢进展者，9 名视为快速进展者。在缓慢进展者中，10 名中的 8 名（80%）的疾病持续时间明显延长，只有 2 名（20%）的疾病持续时间缩短。相比之下，9 名快速进展者中有 5 名的疾病持续时间延长，而 4 名（45%）的疾病持续时间缩短。截至目前，有 4 名患者仍然存活。
本研究是首例对 MSCs 局灶移植治疗 ALS 患者中枢神经系统后生存作为疗效的长期分析，表明 MSC 移植可能减缓 ALS 进展并改善生存。由于临床病程存在个体间差异，根据我们目前的知识水平，我们无法推广这些结果，但这些数据为规划下一代肌萎缩侧索硬化症 MSC 临床试验提供了新的见解。
