Department of Neural Regenerative Medicine, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, 060-8556, Hokkaido, Japan; Department of Advanced Regenerative Therapeutics, Sapporo Medical University School of Medicine, Sapporo, 060-8556, Hokkaido, Japan; Department of Neurology, Yale University School of Medicine, New Haven, CT, 06510, USA.
Department of Orthopaedic Surgery, Sapporo Medical University School of Medicine, Sapporo, 060-8556, Hokkaido, Japan.
Clin Neurol Neurosurg. 2021 Apr;203:106565. doi: 10.1016/j.clineuro.2021.106565. Epub 2021 Feb 18.
Although spinal cord injury (SCI) is a major cause of disability, current therapeutic options remain limited. Recent progress in cellular therapy with mesenchymal stem cells (MSCs) has provided improved function in animal models of SCI. We investigated the safety and feasibility of intravenous infusion of MSCs for SCI patients and assessed functional status after MSC infusion.
In this phase 2 study of intravenous infusion of autologous MSCs cultured in auto-serum, a single infusion of MSCs under Good Manufacturing Practice (GMP) production was delivered in 13 SCI patients. In addition to assessing feasibility and safety, neurological function was assessed using the American Spinal Injury Association Impairment Scale (ASIA), International Standards for Neurological and Functional Classification of Spinal Cord (ISCSCI-92). Ability of daily living was assessed using Spinal Cord Independence Measure (SCIM-III). The study protocol was based on advice provided by the Pharmaceuticals and Medical Devices Agency in Japan. The trial was registered with the Japan Medical Association (JMA-IIA00154).
No serious adverse events were associated with MSC injection. There was neurologic improvement based on ASIA grade in 12 of the 13 patients at six months post-MSC infusion. Five of six patients classified as ASIA A prior to MSC infusion improved to ASIA B (3/6) or ASIA C (2/6), two ASIA B patients improved to ASIA C (1/2) or ASIA D (1/2), five ASIA C patients improved and reached a functional status of ASIA D (5/5). Notably, improvement from ASIA C to ASIA D was observed one day following MSC infusion for all five patients. Assessment of both ISCSCI-92, SCIM-III also demonstrated functional improvements at six months after MSC infusion, compared to the scores prior to MSC infusion in all patients.
While we emphasize that this study was unblinded, and does not exclude placebo effects or a contribution of endogenous recovery or observer bias, our observations provide evidence supporting the feasibility, safety and functional improvements of infused MSCs into patients with SCI.
尽管脊髓损伤（SCI）是导致残疾的主要原因，但目前的治疗选择仍然有限。最近，间充质干细胞（MSCs）的细胞治疗进展为 SCI 动物模型提供了更好的功能。我们研究了 SCI 患者静脉输注 MSCs 的安全性和可行性，并评估了 MSC 输注后的功能状态。
在这项自体血清培养的 MSC 静脉输注的 2 期研究中，对 13 名 SCI 患者进行了单次 GMP 生产的 MSC 输注。除了评估可行性和安全性外，还使用美国脊髓损伤协会损伤量表（ASIA）、国际脊髓损伤神经功能分类标准（ISCSCI-92）评估神经功能。使用脊髓独立性测量量表（SCIM-III）评估日常生活能力。该研究方案基于日本药品和医疗器械管理局的建议。该试验在日本医学协会（JMA-IIA00154）注册。
没有与 MSC 注射相关的严重不良事件。在 MSC 输注后 6 个月，13 名患者中的 12 名患者的 ASIA 分级显示神经功能改善。在 MSC 输注前为 ASIA A 的 6 名患者中有 5 名改善为 ASIA B（3/6）或 ASIA C（2/6），2 名 ASIA B 患者改善为 ASIA C（1/2）或 ASIA D（1/2），5 名 ASIA C 患者改善并达到 ASIA D 的功能状态（5/5）。值得注意的是，所有 5 名患者在 MSC 输注后一天从 ASIA C 改善为 ASIA D。与 MSC 输注前相比，所有患者在 MSC 输注后 6 个月时，ISCSCI-92 和 SCIM-III 的评估也显示出功能改善。
虽然我们强调这项研究是开放性的，不能排除安慰剂效应或内源性恢复或观察者偏倚的贡献，但我们的观察结果为 SCI 患者输注 MSC 的可行性、安全性和功能改善提供了证据支持。
