Investigating the neuroprotective and neuroregenerative properties of bone marrow stem cell mobilising drugs in Friedreich ataxia.

弗里德赖希共济失调（FRDA）是一种进行性神经系统疾病，其特征是活动能力和协调性丧失（共济失调）。它是遗传性共济失调最常见的原因，症状通常在儿童时期变得明显。除了引起神经系统问题外，这种疾病还可能导致心脏和新陈代谢问题。目前还没有任何治疗方法可以减缓，更不用说治愈这种疾病，这种疾病通常会导致成年早期依赖轮椅。干细胞疗法正在开发用于各种神经和非神经疾病，初步证据表明它们可能用于FRDA。我们的初步研究表明，骨髓来源的干细胞对神经细胞和来自FRDA患者的细胞提供保护。这些干细胞也能够改善FRDA引起的一些代谢问题。我们假设，动员FRDA患者骨髓中的干细胞可能是保护体内细胞的一种方式，从而减少由遗传疾病引起的损害。有许多药物可以刺激干细胞从骨髓释放到血液循环中。我们相信这类药物可以通过多种方式发挥作用，而不仅仅是通过动员骨髓干细胞：它们可能对脑细胞有直接的保护作用；它们可能通过刺激已知存在于大脑中的干细胞来促进神经细胞再生；它们也可能促进非神经组织的修复，比如心脏。这些实验效果已在其他退行性神经和心脏疾病的动物模型中被证明是有价值的，它们明显地改善了康复。这些药物已经在常规临床使用（主要用于血液系统疾病，如白血病），这已经为它们的安全性提供了很好的证据，因此有助于加速未来将其用于其他疾病的转化研究。这些药物现在也开始在人体临床试验中进行测试，患者包括运动神经元疾病、中风、阿尔茨海默病、脊髓损伤和心肌梗死。在我们实验室进行的实验研究清楚地表明，骨髓干细胞保护神经细胞并诱导神经系统修复。我们已经证明，人类骨髓干细胞有助于纠正来自FRDA患者的细胞中基因突变的影响（增加FRDA中减少的蛋白frataxin的表达）；增强它们对细胞损伤的抵抗力。我们相信，研究干细胞动员药物是确定神经细胞保护机制的下一个合理步骤。我们的目标是进一步确定神经细胞被这些药物保护或替代的机制。我们将在多种细胞培养和FRDA动物模型中进行测试。将使用骨髓干细胞动员药物的方法转化为临床实践是非常现实的，但在很大程度上取决于我们提出的实验研究，探索和理解这些药物的治疗机制，以便开发一种潜在的简单，非侵入性和有效的神经保护和再生治疗FRDA患者。

Friedreich Ataxia (FRDA) is a progressive neurological illness characterised by loss of mobility and co-ordination (ataxia). It is the commonest cause of inherited ataxia and symptoms usually become apparent in childhood. As well as causing problems in the nervous system, the disease may also lead to heart and metabolism problems. At the present time there are no treatments that can slow down, let alone cure, the condition, which usually leads to wheelchair dependency in early adulthood. Stem cell therapies are being developed for a variety of neurological and non-neurological conditions and preliminary evidence suggests that they may be of use in FRDA. Our initial studies have suggested that bone marrow-derived stem cells offer protection to nerve cells and cells derived from patients with FRDA. These stem cells are also able to improve some of the metabolic problems that FRDA causes. We hypothesise that mobilising stem cells present in the bone marrow of patients with FRDA may be a way of protecting cells within the body and thus reducing damage caused by the genetic disorder. There are a number of drugs that stimulate the release of stem cells from the bone marrow into the blood circulation. We believe that there are multiple ways in which such drugs could help, not just through mobilising bone marrow stem cells: they may have a direct protective effect on brain cells; they may promote nerve cell regeneration by stimulating stem cells known to reside in the brain; and they may also promote repair in non-neurological tissue, such as the heart. These experimental effects have been shown to be valuable in animal models of other degenerative neurological and cardiac disorders, where they clearly improve recovery. Such drugs are already in routine clinical use (mostly for diseases of the blood system, such as leukaemia), which has led to good evidence of their safety, so helping to accelerate future translational research into their use in other conditions. These drugs have also now begun to be tested in human clinical trials in patients with conditions ranging from motor neuron disease, stroke, Alzheimer's disease, and spinal cord injury to myocardial infarction.Experimental studies undertaken within our laboratories clearly indicate bone marrow stem cells protect nerve cells and induce repair of the nervous system. We have demonstrated that human bone marrow stem cells help correct the effects of the genetic mutations in cells derived from patients with FRDA (increasing the expression of the protein, frataxin, which is reduced in FRDA); and increase their resistance to cell damage. We believe that studying stem cell mobilising drugs is the next rational step in defining mechanisms of nerve cell protection. We aim to further determine the mechanisms by which nerve cells may be protected or replaced by these drugs. We will test this in a variety of cell culture and animal models of FRDA. Translating the approach of using bone marrow stem cell mobilising drugs to clinical practice is very realistic, but depends vitally on experimental studies such as those we propose, exploring and understanding the therapeutic mechanisms of these drugs in order to allow the development of a potentially simple, non-invasive and effective neuroprotective and regenerative therapy in patients with FRDA.