Progress in therapy development for amyotrophic lateral sclerosis.
Progress in therapy development for amyotrophic lateral sclerosis.
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DOI：
10.1155/2012/187234
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发表时间：
2012
影响因子：
1.5
通讯作者：
Hensley K
中科院分区：
文献类型：
--
作者：
Venkova-Hristova K;Christov A;Kamaluddin Z;Kobalka P;Hensley K
肌萎缩侧索硬化症 (ALS) 是一种进行性神经退行性疾病，使用任何当前可用的临床工具都无法大幅减缓这种疾病。经过数十年对散发性和家族性 ALS（SALS 和 FALS）的研究，研究人员逐渐认识到 ALS 是一种具有多种遗传和环境病因的复杂综合征。众所周知，ALS 中的运动神经元变性需要在非神经元细胞，尤其是星形胶质细胞和小胶质细胞中发生主动（功能获得）和被动（功能丧失）事件。这些神经炎症过程产生旁分泌因子，对运动神经元产生不利影响，促进蛋白质聚集并损害细胞骨架的完整性。结果是神经元稳态丧失和运动轴突进行性死亡，最终导致受影响的运动神经元死亡。这篇综述将讨论已在小鼠 ALS 模型中进行测试的实验疗法，重点是那些已进展到人体临床试验的疗法。将考虑临床前成功经常未能转化为积极的临床结果的原因。最后，本综述将探讨 ALS 实验治疗的当前趋势，重点关注轴突引导信号通路作为神经细胞骨架结构和功能的药理支持以减缓 ALS 的新靶标的新兴兴趣。
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that cannot be slowed substantially using any currently-available clinical tools. Through decades of studying sporadic and familial ALS (SALS and FALS), researchers are coming to understand ALS as a complex syndrome with diverse genetic and environmental etiologies. It is know appreciated that motor neuron degeneration in ALS requires active (gain of function) and passive (loss of function) events to occur in non-neuronal cells, especially astrocytes and microglia. These neuroinflammatory processes produce paracrine factors that detrimentally affect motor neurons, precipitating protein aggregation and compromising cytoskeletal integrity. The result is a loss of neuronal homeostasis and progressive die-back of motor axons culminating in death of the afflicted motor neurons. This review will discuss experimental therapeutics that have been tested in murine ALS models, with an emphasis on those that have progressed to human clinical trials. Reasons will be considered for the frequent failure of preclinical successes to translate into positive clinical outcomes. Finally, this review will explore current trends in experimental therapeutics for ALS with emphasis on the emerging interest in axon guidance signaling pathways as novel targets for pharmacological support of neural cytoskeletal structure and function in order to slow ALS.