Bone marrow stem cell therapy in multiple sclerosis: potential mechanisms of repair and protection

多发性硬化症（MS）是一种脑和脊髓疾病，影响全球250万人，每年造成欧盟经济90亿欧元的损失，其后果是进行性神经功能障碍。它通常开始于短暂的复发，随后是缓解期，但超过80%的患者会发展为永久性、进行性残疾; 40%的患者在10年内需要轮椅。没有治疗方法可以逆转，停止甚至减缓MS的进行性残疾。干细胞治疗为减少这种不治之症的残疾提供了新的可能性。这些好处将对患者产生巨大的个人影响，也会产生严重的积极经济影响。追求真正的干细胞疗法的紧迫性还在于抵制不受监管的商业干细胞诊所的欺骗性吸引力，这些诊所从绝望的患者那里收取大量资金，用于可疑的，偶尔危险的“治疗”。我们已经探索了几年人类骨髓来源的[BM]干细胞与MS的潜力，最初是在实验室中，最近在一个小的（“一期”）临床试验中。我们专注于这些细胞有很多原因。它们相对容易获得;他们看起来很安全，我们和其他研究已经证实它们具有广泛的有价值的治疗特性。BM中存在各种亚型的干细胞，并且它们似乎具有许多对MS潜在有益的有价值的能力。BM干细胞抑制炎症。它们刺激大脑和脊髓中的其他修复细胞，促进组织修复，并分泌生长因子-保护脑细胞免受损伤。此外，在注射到静脉中后，它们成功地渗透到大脑和脊髓（这是与任何神经系统疾病相关的重要特性，其中进入受影响的脑组织是一个严重的障碍）。最后但并非最不重要的是，患者使用自己的BM细胞进行治疗，避免了组织排斥的严重困难。我们相信这些细胞以多种方式提供帮助，并且不止一种干细胞类型参与治疗效果。在布里斯托，我们最近在6名慢性MS患者中完成了世界上第一个修复性BM细胞治疗的可行性/安全性试验之一（www.nature.com/clpt/journal/v87/n6/full/clpt201044a.html）。安全性得到证实，患者似乎稳定（尽管在这样一个相对短期的研究中，这必须被视为未经证实）。密集的重复测试，测量大脑和脊髓中各种通路的神经传导，显示每个患者在12个月时都有统计学上的显著改善。虽然这些结果是初步的，而且只涉及极少数患者，但至少提高了在受损神经系统中存在显著（尽管非常部分）潜在修复作用的可能性。我们认为这迫切需要进一步的测试--既要加速患者获益，又要开始提高治疗效果。因此，我们提出了一个MS BM干细胞研究计划，包括（1）一个更大的（“二期”）对照试验，治疗70名长期MS患者;和（2）作用机制的平行研究，研究和比较来自治疗的MS患者和对照受试者的BM细胞，确定各种细胞类型中的哪些有助于功效，以及哪些特定的修复机制是重要的。我们的试验得到了美国基金会的资助;这项申请寻求资金来研究这些细胞是如何工作的，重要的是，MS患者的BM细胞和非MS“对照”的BM细胞之间是否存在差异。我们希望这些研究不仅能证实这种方法的治疗益处，还能为改善这种新颖、令人兴奋的治疗方法的规模和影响提供基础。

Multiple sclerosis - MS - is a disease of the brain and spinal cord that affects 2.5m people worldwide, costing the EU economy E9 billion/year, from the consequences of progressive neurological disability. It usually starts with episodes of temporary relapse followed by periods of remission, but over 80% of patients develop permanent, progressive disability; 40% need a wheelchair within 10 years. There are no treatments that reverse, halt or even slow progressive disability in MS.Stem cell therapy offers new possibilities for reducing disability in this incurable disease. Such benefits would have huge personal impact for patients, and also serious positive economic implications. Urgency in pursuing authentic stem cell therapies also lies in countering the deceptive attraction of unregulated commercial stem cell clinics, which take large sums of money from desperate patients for dubious and occasionally hazardous 'treatments'.We have for some years explored the potential of human bone marrow-derived [BM] stem cells in relation to MS, initially in the laboratory, and lately in a small ('phase 1') clinical trial. We concentrate on these cells for many reasons. They are relatively accessible; they appear safe; and our and other studies have confirmed that they have a wide range of valuable therapeutic properties.There are various sub-types of stem cell present within BM, and they appear to possess many valuable capacities of potential benefit for MS. BM stem cells dampen inflammation. They stimulate other repair cells present in the brain and spinal cord, they promote tissue repair, and they secrete growth factors - which protect brain cells against injury. Also, after injection into a vein, they successfully infiltrate the brain and spinal cord (a vital property relating to any neurological disease, where access to affected brain tissue is a serious hurdle). Last but not least, patients are treated using their own BM cells, avoiding the serious difficulties of tissue rejection.We hypothesise that BM cell therapy in longstanding MS offers durable benefit. We believe these cells help in multiple ways, and that more than one stem cell type is involved in the therapeutic effect.In Bristol, we recently completed one of the first feasibility/safety trials in the world of reparative BM cell therapy in 6 patients with chronic MS (www.nature.com/clpt/journal/v87/n6/full/clpt201044a.html). Safety was confirmed, and patients appeared to stabilise (though in such a relatively short term study, this must be viewed as unproven). Intensive repeated tests, measuring nerve conduction in various pathways in the brain and in the spinal cord, showed statistically significant improvements at 12 months in every patient. While highly preliminary and involving only a very small number of patients, these results at least raise the possibility of a significant (though very partial) underlying repair effect within the damaged nervous system.We believe this urgently requires further testing - both to accelerate benefit towards patients, and to begin improving therapeutic efficacy. We therefore propose a programme of MS BM stem cell research, including (1) a much larger ('phase two') controlled trial, treating 70 patients with longstanding MS; and (2) a parallel study of the mechanisms of action, studying and comparing BM cells from treated MS patients and control subjects, establishing which of the various cell types contribute to efficacy, and which specific repair mechanism(s) are important. Our trial has been funded by a grant from a USA foundation; this application seeks funding to carry out studies into how these cells work - and, importantly, whether there are differences between BM cells from MS patients and those from non-MS 'controls'. We hope these studies will not only confirm the therapeutic benefit of this approach, but also provide the basis for improving the magnitude and impact of this novel, exciting treatment.