Worldwide Discovery Research, Cephalon, Inc., West Chester, PA 19380, USA.
Biochem Pharmacol. 2011 Jun 15;81(12):1422-34. doi: 10.1016/j.bcp.2011.01.021. Epub 2011 Feb 3.
The need to develop effective treatments for Alzheimer's disease has been confounded by repeated clinical failures where promising new chemical entities that have been extensively characterized in preclinical models of Alzheimer's disease have failed to show efficacy in the human disease state. This has been attributed to: the selection of drug targets that have yet to be shown as causal to the disease as distinct from being the result of the disease process, a lack of congruence in the animal models of Alzheimer's disease, wild-type and transgenic, to the human disease, and the enrollment of patients in proof of concept clinical trials who are at too advanced a stage of the disease to respond to any therapeutic. The development of validated biomarkers that can be used for disease diagnosis and progression is anticipated to improve patient enrollment in clinical trials, to develop new animal models and to identify new disease targets for drug discovery. The present review assesses the status of current efforts in developing CSF biomarkers for Alzheimer's disease and briefly discusses the status of CSF biomarker efforts in schizophrenia, depression, Parkinson's disease and multiple sclerosis.
由于在阿尔茨海默病的临床前模型中得到广泛表征的有前景的新化学实体未能在人类疾病状态中显示出疗效，因此需要开发有效的阿尔茨海默病治疗方法，但这一目标一再受挫。这归因于：药物靶点的选择尚未被证明与疾病有关，而与疾病过程的结果不同；阿尔茨海默病的动物模型，野生型和转基因型与人类疾病之间缺乏一致性；以及在概念验证临床试验中招募的患者处于疾病的晚期阶段，无法对任何治疗产生反应。预计经过验证的生物标志物的开发可用于疾病诊断和进展，以改善临床试验中的患者招募，开发新的动物模型并确定药物发现的新疾病靶点。本综述评估了目前开发阿尔茨海默病 CSF 生物标志物的进展情况，并简要讨论了 CSF 生物标志物在精神分裂症、抑郁症、帕金森病和多发性硬化症中的进展情况。
