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

Friedreich共济失调(FRDA)是一种进行性神经系统疾病，特征是缺乏灵活性和协调性(共济失调)。这是遗传性共济失调的最常见原因，症状通常在儿童时期就显现出来。除了导致神经系统问题外，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这种疾病，更不用说治愈了，这种疾病通常会导致成年初期对轮椅的依赖。干细胞疗法正在为各种神经和非神经疾病开发，初步证据表明，它们可能在FRDA中使用。我们的初步研究表明，骨髓来源的干细胞为神经细胞和来自FRDA患者的细胞提供保护。这些干细胞还能够改善FRDA引起的一些新陈代谢问题。我们假设，动员存在于FRDA患者骨髓中的干细胞可能是保护体内细胞从而减少遗传疾病造成的损害的一种方式。有许多药物可以刺激干细胞从骨髓释放到血液循环中。我们认为，这些药物可以通过多种方式提供帮助，不仅仅是通过动员骨髓干细胞：它们可能对脑细胞有直接保护作用；它们可能通过刺激已知驻留在大脑中的干细胞促进神经细胞再生；它们还可能促进非神经组织的修复，如心脏。这些实验效应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，在这些动物模型中，它们明显地促进了康复。这类药物已经在常规临床上使用(主要用于血液系统疾病，如白血病)，这导致了它们安全性的良好证据，因此有助于加快未来对它们在其他情况下使用的转化性研究。这些药物现在也开始在运动神经元病、中风、阿尔茨海默病、脊髓损伤到心肌梗死等疾病的患者身上进行临床试验。我们实验室内进行的实验研究清楚地表明，骨髓干细胞保护神经细胞，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患者的细胞中的基因突变的影响(增加FRDA中蛋白质Frataxin的表达)；并增强其对细胞损伤的抵抗力。我们认为，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可能被这些药物保护或取代的机制。我们将在FRDA的各种细胞培养和动物模型中测试这一点。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，但关键取决于我们提出的实验研究，探索和了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疗法。

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.