Targeting abnormal metabolism in Alzheimer's disease: The Drug Repurposing for Effective Alzheimer's Medicines (DREAM) study.
Targeting abnormal metabolism in Alzheimer's disease: The Drug Repurposing for Effective Alzheimer's Medicines (DREAM) study.
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DOI：
10.1002/trc2.12095
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Thambisetty M
中科院分区：
文献类型：
--
作者：
Desai RJ;Varma VR;Gerhard T;Segal J;Mahesri M;Chin K;Nonnenmacher E;Gabbeta A;Mammen AM;Varma S;Horton DB;Kim SC;Schneeweiss S;Thambisetty M
基于实验动物模型的传统范式的阿尔茨海默病和相关痴呆(ADRD)的疾病修改疗法的药物发现一直令人失望。我们描述了药物再用途有效阿尔茨海默病药物(DREAM)研究的原理和设计，这是传统药物发现的一个创新的多学科替代方案。首先，我们在假说生成阶段使用系统生物学的观点来识别代谢异常，这些代谢异常可能先于ADRD神经病理的积累或与其相互作用，加速疾病的临床症状的表达。其次，在“假设完善”阶段，我们建议使用大的患者队列来测试被批准用于其他适应症的药物是否可能改变疾病的发展轨迹，这些药物也针对ADRD发病的代谢驱动因素。我们强调以人群为基础的药物流行病学研究的关键挑战，旨在量化药物使用和ADRD发病之间的联系，并概述可靠的因果推断原则，以防止常见陷阱。从这种方法中产生的候选ADRD疗法将有望成为可信的疾病修改疗法，供随机对照试验评估。
Drug discovery for disease‐modifying therapies for Alzheimer's disease and related dementias (ADRD) based on the traditional paradigm of experimental animal models has been disappointing. We describe the rationale and design of the Drug Repurposing for Effective Alzheimer's Medicines (DREAM) study, an innovative multidisciplinary alternative to traditional drug discovery. First, we use a systems biology perspective in the "hypothesis generation" phase to identify metabolic abnormalities that may either precede or interact with the accumulation of ADRD neuropathology, accelerating the expression of clinical symptoms of the disease. Second, in the "hypothesis refinement" phase we propose use of large patient cohorts to test whether drugs approved for other indications that also target metabolic drivers of ADRD pathogenesis might alter the trajectory of the disease. We emphasize key challenges in population‐based pharmacoepidemiologic studies aimed at quantifying the association between medication use and ADRD onset and outline robust causal inference principles to safeguard against common pitfalls. Candidate ADRD treatments emerging from this approach will hold promise as plausible disease‐modifying therapies for evaluation in randomized controlled trials.
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影响因子：
7.2
作者：
Hernan, Miguel A.;Sauer, Brian C.;Shrier, Ian
通讯作者：
Shrier, Ian
DOI：
10.18553/jmcp.2014.20.11.1110
发表时间：
2014-11-01
影响因子：
2.1
作者：
Desai, Rishi J.;Rao, Jaya K.;Farley, Joel F.
通讯作者：
Farley, Joel F.
影响因子：
29
作者：
Gomm, Willy;von Holt, Klaus;Haenisch, Britta
通讯作者：
Haenisch, Britta
DOI：
10.1016/j.jalz.2013.11.006
发表时间：
2014-11
期刊：
Alzheimer's & dementia : the journal of the Alzheimer's Association
影响因子：
--
作者：
Barnes DE;Beiser AS;Lee A;Langa KM;Koyama A;Preis SR;Neuhaus J;McCammon RJ;Yaffe K;Seshadri S;Haan MN;Weir DR
通讯作者：
Weir DR
影响因子：
5.9
作者：
Brilliant, Murray H.;Vaziri, Kamyar;McKay, Brian S.
通讯作者：
McKay, Brian S.