Transplantation of genetically modified haematopoietic stem cells for Friedreich's Ataxia

弗里德赖希共济失调症（FA）是一种无法治愈的神经系统疾病，通常出现在儿童晚期。患有此病的人会经历神经功能障碍的进行性积累，包括肌肉协调受损、无力、不平衡以及语言、吞咽、听力、视觉和感觉困难。它是由卵黄蛋白基因（FXN）的基因突变引起的，该基因携带一种叫做卵黄蛋白的蛋白质的遗传密码，导致全身细胞中卵黄蛋白水平低，导致细胞功能失调，最终死亡。有许多研究在寻找可能的FA新疗法，但是，到目前为止，FA患者仍然没有任何治疗来限制疾病的进展。我们的研究小组在与FA患者具有相同基因突变的小鼠身上进行了骨髓干细胞移植实验。当我们将这些FA小鼠与从具有正常版本FXN基因的供体小鼠中提取的BM干细胞移植时，它们的疾病指标显着改善，运动，平衡，协调和神经细胞存活得到改善。有趣的是，我们可以追踪移植的骨髓干细胞，发现大量这些细胞已经进入受FA影响的神经系统部分，并帮助保护和修复受伤的神经细胞。我们目前正在开发骨髓干细胞治疗FA，最近在FA患者中进行了一项临床试验，研究骨髓细胞被激活并释放到血液中的程度，希望它们能帮助神经细胞修复。这项试验的结果非常令人鼓舞；我们现在想把我们的研究推进到FA患者的最终治疗。虽然实验证据表明骨髓干细胞移植作为FA的有效治疗方法是可行的，但在临床上使用时，从一个人的骨髓移植健康干细胞并将其转移到另一个人（称为同种异体移植）存在巨大的风险；寻找合适的免疫系统匹配的骨髓移植供体的挑战，使用强效药物抑制免疫系统（导致严重的并发症，如心脏病、神经损伤和感染/败血症），严重贫血的风险以及移植细胞攻击体内其他细胞引起的危及生命的并发症，这些都是可能的。为了避免同种异体骨髓干细胞移植的主要风险，我们提出了一种替代方法，即从FA患者身上取出干细胞，并使用基因工程技术将新的FXN基因插入这些细胞的DNA中。这些干细胞携带正常版本的FXN基因，然后可以移植回患者体内，进入骨髓、血液和神经系统，然后保护和修复其他细胞。在临床试验之前，在FA动物模型中充分阐明该方法的生物学机制、安全性和有效性是开发这种治疗方法的关键前期阶段。该项目将利用尖端技术，在骨髓干细胞中植入新的FXN基因，然后将其移植到与FA患者基因异常相同的小鼠体内。这些小鼠将被监测以评估移植对FA疾病进展的影响。我们还将开发一种将FXN输送到人类骨髓细胞的技术，以确保这可以在人类细胞中安全有效地完成。根据这项研究，我们将在FA患者中开展新的临床试验。骨髓干细胞移植治疗转化为临床实践具有现实意义；50多年来，这种方法已经成功地应用于人类治疗其他疾病。我们相信，我们的方法为患有这种无法治愈和无法治疗的疾病的人提供了治疗选择方面的重大进步。

Friedreich's ataxia (FA) is an incurable neurological disorder, typically presenting in late childhood. People with the condition experience progressive accumulation of neurological disability with impaired muscle coordination, weakness, imbalance and difficulties with speech, swallowing, hearing, vision and sensation. It is caused by a genetic mutation in the frataxin gene (FXN), which carries the genetic code for a protein called frataxin, resulting in low levels of frataxin within cells throughout the body causing them to malfunction and eventually die. There have numerous studies looking at possible new therapies for FA, but, as yet, people with FA remain without any treatment to limit disease progression. Our research group have performed bone marrow (BM) stem cell transplantation experiments in mice that have the same genetic mutation as people with FA. When we transplant these FA mice with BM stem cells taken from donor mice with a normal version of the FXN gene, their indicators of disease improve significantly, with improvements in movement, balance, coordination and nerve cell survival. Interestingly, we can track the transplanted BM stem cells and find that large numbers of these cells have travelled into parts of the nervous system affected by FA and helped to protect and repair injured nerve cells. We are currently developing BM stem cell treatments for FA, having recently performed a clinical trial in people with FA looking at how well BM cells can be activated and released into the blood stream with a hope they aid nerve cell repair. The results of this trial are very encouraging; we now want to move our research forward to a definitive treatment for people with FA. Although experimental evidence demonstrates the feasibility of BM stem cell transplantation as an effective therapy for FA, when used clinically, transplanting healthy stem cells from the BM of one person and transferring them to another (called a allogeneic transplant) is associated with hugely significant risks; the challenge of finding an appropriately immune system matched BM donor, the use of powerful drugs to suppress the immune system (resulting in serious complications such as heart disease, neurological injury and infection/sepsis), the risk of severe anaemia and life-threatening complications arising from transplanted cells attacking other cells in the body all remain a possibility. To avoid the major risks of allogeneic BM stem cell transplantation, we propose an alternative approach through removing stem cells from a person with FA and inserting a new FXN gene into the DNA of these cells using genetic engineering techniques. These stem cells, carrying a normal version of the FXN gene, can then be transplanted back into that person to enter the BM, blood and nervous system to then protect and repair to other cells. A vital preliminary stage in the development of this treatment is to fully elucidate the biological mechanisms, safety and efficacy of the approach in an animal model of FA prior to clinical trials. This project will use state-of-the-art technology to insert a new FXN gene into BM stem cells prior to transplanting them into mice containing the same genetic abnormality as people with FA. These mice will be monitored to assess the impact transplantation has on FA disease progression. We will also develop a technique to deliver the FXN to human BM cells to ensure this can be done safely and efficiently in human cells. Following on from this study, we will be in a position to develop new clinical trials in people with FA. Translation of BM stem cell transplantation therapy to clinical practice is realistic; the procedure has been successfully applied in humans for other diseases for over 50 years. We believe that our approach offers a significant advance in therapeutic options for people with this otherwise incurable and untreatable disease.