Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
J Neurol Neurosurg Psychiatry. 2012 Mar;83(3):329-35. doi: 10.1136/jnnp-2011-301307.
Recent advancements in neurobiology have provided increasing insights into the pathophysiology of neurodegenerative diseases, and opened doors to the development of molecular targeted therapies. Although many compounds showed positive results in animal studies, there is almost no drug for which the efficacy has been confirmed in clinical trials. This failure reflects a number of unsolved problems: limited knowledge of the exact pathways of neuron loss; safety and delivery issues of compounds; lack of established animal models that faithfully recapitulate human pathology; lack of validated, sensitive outcome measures; and limited tools to diagnose pre-symptomatic patients. To investigate the efficacy of potential disease modifying agents with limited financial and patient resources, the efficiency of both basic and clinical studies should be improved by integrated approaches. The reproduction of positive results from animal experiments that analyse the efficacy of compounds at symptomatic stages is needed to improve the credibility of preclinical studies. To effectuate proof of concept processes, novel designs of phase 2 clinical trials, such as the futility study, are being developed. Given the modest effects of molecular targeted therapies in human, it is necessary to explore clinical outcome measures that are resistant to variability, subjectivity and placebo. Furthermore, there is an increasing need for testing interventions before the onset of symptoms. Analyses of natural histories of biological and neurophysiological markers may provide indispensable information for designing such preventive trials. As it is now clear that conventional approaches are not necessarily appropriate for the development of molecular targeted therapies, both basic and clinical studies require conceptual innovation.
神经生物学的最新进展为神经退行性疾病的病理生理学提供了越来越多的深入了解，并为分子靶向治疗的发展开辟了道路。尽管许多化合物在动物研究中显示出积极的结果，但几乎没有一种药物在临床试验中被证实有效。这种失败反映了许多未解决的问题：对神经元丧失的确切途径的了解有限；化合物的安全性和输送问题；缺乏能够忠实地重现人类病理学的既定动物模型；缺乏经过验证的、敏感的结果测量方法；以及用于诊断无症状患者的有限工具。为了用有限的财务和患者资源研究潜在的疾病修饰剂的疗效，应通过综合方法提高基础和临床研究的效率。需要复制在有症状阶段分析化合物疗效的动物实验中的阳性结果，以提高临床前研究的可信度。为了实现概念验证过程，正在开发新的 2 期临床试验设计，如无效性研究。鉴于分子靶向治疗在人类中的作用有限，有必要探索对变异性、主观性和安慰剂具有抗性的临床结果测量方法。此外，有必要在出现症状之前测试干预措施。对生物和神经生理学标志物的自然史进行分析可能为设计此类预防试验提供不可或缺的信息。由于现在很清楚，传统方法不一定适用于分子靶向治疗的开发，因此基础和临床研究都需要概念创新。
