Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.
Lancet Neurol. 2012 Feb;11(2):150-6. doi: 10.1016/S1474-4422(11)70305-2. Epub 2012 Jan 10.
More than half of patients with multiple sclerosis have progressive disease characterised by accumulating disability. The absence of treatments for progressive multiple sclerosis represents a major unmet clinical need. On the basis of evidence that mesenchymal stem cells have a beneficial effect in acute and chronic animal models of multiple sclerosis, we aimed to assess the safety and efficacy of these cells as a potential neuroprotective treatment for secondary progressive multiple sclerosis.
Patients with secondary progressive multiple sclerosis involving the visual pathways (expanded disability status score 5·5-6·5) were recruited from the East Anglia and north London regions of the UK. Participants received intravenous infusion of autologous bone-marrow-derived mesenchymal stem cells in this open-label study. Our primary objective was to assess feasibility and safety; we compared adverse events from up to 20 months before treatment until up to 10 months after the infusion. As a secondary objective, we chose efficacy outcomes to assess the anterior visual pathway as a model of wider disease. Masked endpoint analyses was used for electrophysiological and selected imaging outcomes. We used piecewise linear mixed models to assess the change in gradients over time at the point of intervention. This trial is registered with ClinicalTrials.gov, number NCT00395200.
We isolated, expanded, characterised, and administered mesenchymal stem cells in ten patients. The mean dose was 1·6×10(6) cells per kg bodyweight (range 1·1-2·0). One patient developed a transient rash shortly after treatment; two patients had self-limiting bacterial infections 3-4 weeks after treatment. We did not identify any serious adverse events. We noted improvement after treatment in visual acuity (difference in monthly rates of change -0·02 logMAR units, 95% CI -0·03 to -0·01; p=0·003) and visual evoked response latency (-1·33 ms, -2·44 to -0·21; p=0·020), with an increase in optic nerve area (difference in monthly rates of change 0·13 mm(2), 0·04 to 0·22; p=0·006). We did not identify any significant effects on colour vision, visual fields, macular volume, retinal nerve fibre layer thickness, or optic nerve magnetisation transfer ratio.
Autologous mesenchymal stem cells were safely given to patients with secondary progressive multiple sclerosis in our study. The evidence of structural, functional, and physiological improvement after treatment in some visual endpoints is suggestive of neuroprotection.
Medical Research Council, Multiple Sclerosis Society of Great Britain and Northern Ireland, Evelyn Trust, NHS National Institute for Health Research, Cambridge and UCLH Biomedical Research Centres, Wellcome Trust, Raymond and Beverly Sackler Foundation, and Sir David and Isobel Walker Trust.
超过一半的多发性硬化症患者患有以残疾累积为特征的进行性疾病。没有针对进展性多发性硬化症的治疗方法，这是一个未满足的主要临床需求。基于间充质干细胞在急性和慢性多发性硬化症动物模型中具有有益作用的证据，我们旨在评估这些细胞作为潜在的神经保护治疗方法，用于治疗继发进展性多发性硬化症。
我们从英国东安格利亚和伦敦北部地区招募了涉及视觉通路的继发进展性多发性硬化症患者（扩展残疾状态评分 5.5-6.5）。在这项开放标签研究中，参与者接受了自体骨髓来源的间充质干细胞静脉输注。我们的主要目标是评估可行性和安全性；我们比较了治疗前最多 20 个月至输注后最多 10 个月的不良事件。作为次要目标，我们选择了疗效结果来评估前视通路作为更广泛疾病的模型。对电生理和选定的成像结果进行了盲法终点分析。我们使用分段线性混合模型来评估在干预点随时间变化的梯度变化。这项试验在 ClinicalTrials.gov 注册，编号为 NCT00395200。
我们在 10 名患者中分离、扩增、表征和施用了间充质干细胞。平均剂量为 1.6×10(6)个细胞/公斤体重（范围 1.1-2.0）。一名患者在治疗后不久出现短暂皮疹；两名患者在治疗后 3-4 周出现自限性细菌感染。我们没有发现任何严重的不良事件。我们注意到治疗后视力（每月变化率差异-0.02 对数 MAR 单位，95%CI-0.03 至-0.01；p=0.003）和视觉诱发电位潜伏期（-1.33 毫秒，-2.44 至-0.21；p=0.020）的改善，视神经面积增加（每月变化率差异 0.13 毫米(2)，0.04 至 0.22；p=0.006）。我们没有发现任何对色觉、视野、黄斑体积、视网膜神经纤维层厚度或视神经磁化传递比有任何显著影响。
在我们的研究中，自体间充质干细胞安全地给予了继发进展性多发性硬化症患者。一些视觉终点在治疗后结构、功能和生理改善的证据表明具有神经保护作用。
医学研究理事会、大不列颠及北爱尔兰多发性硬化症协会、伊芙琳信托基金会、英国国民健康保险制度国家卫生研究院、剑桥大学和 UCLH 生物医学研究中心、惠康信托基金会、雷蒙德和贝弗利·萨克勒基金会以及大卫和伊泽贝尔·沃克信托基金会。
