Autologous mesenchymal stem cells for the treatment of secondary progressive multiple sclerosis: an open-label phase 2a proof-of-concept study.
Autologous mesenchymal stem cells for the treatment of secondary progressive multiple sclerosis: an open-label phase 2a proof-of-concept study.
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DOI：
10.1016/s1474-4422(11)70305-2
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发表时间：
2012-02
期刊：
影响因子：
48
通讯作者：
Chandran, Siddharthan
中科院分区：
文献类型：
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作者：
Connick, Peter;Kolappan, Madhan;Crawley, Charles;Webber, Daniel J.;Patani, Rickie;Michell, Andrew W.;Du, Ming-Qing;Luan, Shi-Lu;Altmann, Daniel R.;Thompson, Alan J.;Compston, Alastair;Scott, Michael A.;Miller, David H.;Chandran, Siddharthan
超过一半的多发性硬化症患者具有以累积残疾为特征的进行性疾病。进行性多发性硬化症治疗的缺乏代表了一个主要的未满足的临床需求。基于间充质干细胞在急性和慢性多发性硬化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继发性进展性多发性硬化潜在神经保护治疗的安全性和有效性。从英国东英吉利和北伦敦地区招募了累及视觉通路的继发性进展型多发性硬化症患者（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间充质干细胞的静脉输注。我们的主要目的是评估可行性和安全性;我们比较了治疗前20个月至输注后10个月的不良事件。作为次要目的，我们选择疗效结局来评估前部视觉通路作为更广泛疾病的模型。对电生理和选定的成像结局进行了掩蔽终点分析。我们使用分段线性混合模型来评估干预点梯度随时间的变化。本试验在ClinicalTrials.gov注册，编号NCT 00395200。我们在10名患者中分离、扩增、鉴定和管理间充质干细胞。平均剂量为1.6 ×106个细胞/kg体重（范围1.1 - 2.0）。1例患者在治疗后不久出现一过性皮疹; 2例患者在治疗后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的改善（月变化率差异为−0·02 logMAR单位，95% CI为−0·03至−0·01; p=0·003）和视觉诱发反应潜伏期（−1·33 ms，−2·44至−0·21; p=0·020），视神经面积增加（月变化率差异为0·13 mm 2，0·04至0·22; p=0·006）。我们没有发现对色觉、视野、黄斑体积、视网膜神经纤维层厚度或视神经磁化转移率有任何显著影响。在我们的研究中，自体间充质干细胞安全地给予继发性进展型多发性硬化症患者。治疗后某些视觉终点的结构、功能和生理改善的证据提示了神经保护作用。医学研究理事会、大不列颠和北方爱尔兰多发性硬化症协会、伊夫林信托基金会、NHS国家健康研究所、剑桥和UCLH生物医学研究中心、威康信托基金会、雷蒙德和贝弗利萨克勒基金会以及大卫爵士和伊泽贝尔步行者信托基金会。
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 1·6×106 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 mm2, 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.