Testing the right target and right drug at the right stage.
Testing the right target and right drug at the right stage.
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DOI：
10.1126/scitranslmed.3002609
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发表时间：
2011-11-30
影响因子：
17.1
通讯作者：
Aisen PS
中科院分区：
文献类型：
--
作者：
Sperling RA;Jack CR Jr;Aisen PS
阿尔茨海默病(AD)是目前还没有疾病修正疗法的唯一主要死亡原因。最近AD痴呆阶段令人失望的试验结果对我们目前开发疾病改良剂的方法提出了多个问题。越来越多的证据表明，阿尔茨海默病的病理生理过程在痴呆发病前许多年就开始了。那么，为什么我们一直在针对疾病过程的初始阶段在疾病末期的患者身上测试药物呢？阿尔茨海默病(AD)仍然是老龄化最可怕的后果之一，65岁以上的人中每十个人中就有一个以上受到影响。仅在美国，婴儿潮一代每天就有1万多人年满65岁，我们真的面临着AD流行病。在过去的十年中，一系列令人失望的临床试验结果引发了人们对我们目前开发AD修饰疗法的战略的担忧。有三个假设可以解释最近AD试验的失败：(I)我们针对的是错误的病理生理机制；(Ii)药物没有与患者预期的目标相结合；(Iii)药物正在击中正确的目标，但在疾病的错误阶段这样做。在这里，我们解决了第三个假设，并建议特定的基于淀粉样蛋白的治疗应针对AD的早期阶段，甚至可能在临床症状出现之前。此外，我们认为该领域有足够的工具在无症状的个体中开始“二级预防”试验，这些个体具有发展为认知障碍和阿尔茨海默病的高风险。
Alzheimer’s disease (AD) is the only leading cause of death for which no disease-modifying therapy is currently available. Recent disappointing trial results at the dementia stage of AD have raised multiple questions about our current approaches to the development of disease-modifying agents. Converging evidence suggests that the pathophysiological process of AD begins many years before the onset of dementia. So why do we keep testing drugs aimed at the initial stages of the disease process in patients at the end-stage of the illness? Alzheimer’s disease (AD) remains one of the most feared consequences of aging, affecting more than one out of every ten individuals over the age of 65. With more than 10,000 baby boomers turning 65 every day in the United States alone, we are truly facing an AD epidemic. Over the past decade, a string of disappointing clinical trial results have raised concerns about our current strategy for development of AD-modifying therapies. Three hypotheses can explain these recent AD trial failures: (i) We are targeting the wrong pathophysiological mechanisms; (ii) The drugs do not engage the intended targets in patients; and (iii) The drugs are hitting the right targets, but are doing so at the wrong stage of the disease. Here, we address the third supposition and suggest that specific amyloid-based therapies be directed at much earlier stages of ADperhaps even prior to the emergence of clinical symptoms. Furthermore, we argue that the field has sufficient tools to begin “secondary prevention” trials in asymptomatic individuals whoare at high risk for progression to cognitive impairment and AD dementia.
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影响因子：
9.9
作者：
Ringman, J. M.;Younkin, S. G.;Cummings, J. L.
通讯作者：
Cummings, J. L.
影响因子：
9.9
作者：
Li, G.;Sokal, I.;Montine, T. J.
通讯作者：
Montine, T. J.
影响因子：
16.2
作者：
Oddo, S;Billings, L;LaFerla, FM
通讯作者：
LaFerla, FM
影响因子：
4.2
作者：
Forsberg, Anton;Engler, Henry;Nordberg, Agneta
通讯作者：
Nordberg, Agneta
影响因子：
11.2
作者：
Rentz, Dorene M.;Locascio, Joseph J.;Becker, John A.;Moran, Erin K.;Eng, Elisha;Buckner, Randy L.;Sperling, Reisa A.;Johnson, Keith A.
通讯作者：
Johnson, Keith A.