Neural and glial progenitor transplantation as a neuroprotective strategy for Amyotrophic Lateral Sclerosis (ALS).
Neural and glial progenitor transplantation as a neuroprotective strategy for Amyotrophic Lateral Sclerosis (ALS).
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DOI：
10.1016/j.brainres.2015.06.035
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发表时间：
2015-12-02
期刊：
影响因子：
2.9
通讯作者：
中科院分区：
文献类型：
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ALS是一种神经退行性疾病，患病率高达7.4/100，000，终生发生ALS的总体风险为1：400。大多数患者死于进行性虚弱后的呼吸衰竭。到目前为止，只有一种传统的药物-利鲁唑，已被证明可以提供生存的好处，但许多药物干预措施已在临床前模型的ALS没有随后转化为患者的疗效进行了研究。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，非神经元细胞显著促进神经元功能障碍和死亡。干细胞移植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，最近的研究、临床前努力和早期临床试验更实际地集中在神经干细胞、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，许多研究已经显示了通过各种不同的机制的神经保护作用，包括神经营养因子分泌、谷氨酸转运蛋白调节和神经炎症调节等。然而，鉴于细胞替代可能涉及许多生物学相关因素，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和运动神经元疾病传播之间的相互作用，用正常细胞替换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将细胞递送到神经轴疾病相关区域的最合适的方法和途径，细胞存活和迁移，以及移植后跟踪细胞。将干细胞移植到ALS患者中的最初发展的核心是证明移植的细胞缺乏致瘤性并具有适当的生物分布，以确保ALS患者接受这些治疗的安全性。在这里，我们回顾了临床前和临床研究的重点是神经和胶质祖细胞移植作为一个有前途的神经保护治疗ALS。干细胞移植神经保护的基本原理，概念验证动物研究，以及目前面临的挑战，这些疗法的翻译到临床。最后，我们讨论了包括诱导多能干细胞技术和移植后细胞跟踪和检测的发展在内的进展。随着首次在美国安全完成脊髓内干细胞移植治疗ALS的人体I期临床试验，干细胞疗法被转化为临床的时机已经成熟，令人兴奋的是，评估ALS的神经保护作用。
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.
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