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Neural and glial progenitor transplantation as a neuroprotective strategy for Amyotrophic Lateral Sclerosis (ALS)

机译：神经和神经胶质祖细胞移植作为肌萎缩性侧索硬化症（ALS）的神经保护策略

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ALS is a neurodegenerative disease with a prevalence rate of up to 7.4/100,000 and the overall risk of developing ALS over a lifetime is 1:400. Most patients die from respiratory failure following a course of progressive weakness. To date, only one traditional pharmaceutical agent-riluzole, has been shown to afford a benefit on survival but numerous pharmaceutical interventions have been studied in preclinical models of ALS without subsequent translation to patient efficacy. Despite the relative selectivity of motor neuron cell death, animal and tissue culture models of familial ALS suggest that non-neuronal cells significantly contribute to neuronal dysfunction and death. Early efforts to transplant stem cells had focused on motor neuron replacement. More practically for this aggressive neurodegenerative disease, recent studies, preclinical efforts, and early clinical trials have focused on the transplantation of neural stem cells, mesenchymal stem cells, or glial progenitors. Using transgenic mouse or rat models of ALS, a number of studies have shown neuroprotection through a variety of different mechanisms that have included neurotrophic factor secretion, glutamate transporter regulation, and modulation of neuroinflammation, among others. However, given that cell replacement could involve a number of biologically relevant factors, identifying the key pathway(s) that may contribute to neuroprotection remains a challenge. Nevertheless, given the abundant data supporting the interplay between non-neuronal cell types and motor neuron disease propagation, the replacement of disease-carrying host cells by normal cells may be sufficient to confer neuroprotection. Key preclinical issues that currently are being addressed include the most appropriate methods and routes for delivery of cells to disease-relevant regions of the neuraxis, cell survival and migration, and tracking the cells following transplantation. Central to the initial development of stem cell transplantation into patients with ALS is the demonstration that transplanted cells lack tumorigenicity and have the appropriate biodistribution to ensure the safety of ALS patients receiving these therapies. Here, we review preclinical and clinical studies focusing on the transplantation of neural and glial progenitor cells as a promising neuroprotective therapy for ALS. The rationale for stem cell transplantation for neuroprotection, proof-of-concept animal studies, and current challenges facing translation of these therapies to the clinic is presented. Lastly, we discuss advancements on the horizon including induced pluripotent stem cell technology and developments for cellular tracking and detection post-transplantation. With the safe completion of the first-in-human Phase I clinical trial for intraspinal stem cell transplantation for ALS in the United States, the time is ripe for stem cell therapies to be translated to the clinic and excitingly, evaluated for neuroprotection for ALS. This article is part of a Special Issue entitled SI: Neuroprotection. (C) 2015 Elsevier B.V. All rights reserved.
机译：ALS是一种神经退行性疾病，患病率高达7.4 / 100,000，一生中患ALS的总风险为1：400。大多数患者在进行性无力的过程中死于呼吸衰竭。迄今为止，已显示仅一种传统的药物利鲁唑对生存有益处，但是已经在ALS的临床前模型中研究了许多药物干预措施，而没有随后转化为患者的疗效。尽管运动神经元细胞死亡具有相对选择性，但家族性ALS的动物和组织培养模型表明，非神经元细胞显着促进神经元功能障碍和死亡。移植干细胞的早期努力集中在运动神经元替代上。对于这种侵袭性神经退行性疾病，更实际的是，最近的研究，临床前努力和早期临床试验都集中在神经干细胞，间充质干细胞或神经胶质祖细胞的移植上。使用ALS的转基因小鼠或大鼠模型，许多研究显示神经保护作用是通过多种不同的机制实现的，这些机制包括神经营养因子的分泌，谷氨酸转运蛋白的调节和神经炎症的调节等。但是，鉴于细胞置换可能涉及许多生物学相关因素，因此确定可能有助于神经保护的关键途径仍然是一个挑战。然而，鉴于大量数据支持非神经元细胞类型与运动神经元疾病传播之间的相互作用，用正常细胞替代携带疾病的宿主细胞可能足以赋予神经保护作用。目前正在解决的关键临床前问题包括最合适的方法和途径，用于将细胞递送至神经疾病的相关区域，细胞存活和迁移，以及在移植后追踪细胞。干细胞移植入ALS患者最初发展的中心是证明移植细胞缺乏致瘤性，并具有适当的生物分布以确保接受这些疗法的ALS患者的安全。在这里，我们回顾临床前和临床研究，侧重于神经和神经胶质祖细胞的移植，作为有希望的ALS神经保护疗法。介绍了用于神经保护的干细胞移植的原理，概念验证的动物研究以及将这些疗法转化为临床所面临的当前挑战。最后，我们讨论了地平线的发展，包括诱导多能干细胞技术以及移植后细胞跟踪和检测的发展。在美国，安全完成了针对脊髓内干细胞移植进行ALS的人类首次I期临床试验后，将干细胞疗法应用于临床并进行令人兴奋的评估ALS的神经保护的时机已经成熟。本文是名为《 SI：神经保护》的一期特刊的一部分。 （C）2015 Elsevier B.V.保留所有权利。

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