Casas Ana I, Nogales Cristian, Szepanowski Rebecca D, Elbatreek Mahmoud H, Anastasi Elisa, Sadegh Sepideh, Skelton James, Frank Benedikt, Wipat Anil, Baumbach Jan, Kleinschnitz Christoph, Schmidt Harald H H W
Department of Neurology and Center for Translational Neuro- and Behavioral Sciences (C-TNBS) University Medicine Essen Essen Germany.
Department of Pharmacology and Personalised Medicine School of Mental Health and Neuroscience, Faculty of Health, Medicine and Life Sciences, Maastricht University Maastricht The Netherlands.
J Am Heart Assoc. 2025 May 20;14(10):e039098. doi: 10.1161/JAHA.124.039098. Epub 2025 May 15.
Most human disease definitions, except for rare and communicable diseases, are based on symptoms in specific organs, not on causal molecular mechanisms. This limits treatments to imprecise symptomatic approaches with high numbers needed to treat. Systems medicine, instead, has a holistic approach and defines diseases in an organ-agnostic manner on the basis of associated risk genes, their encoded proteins, and protein-protein interactions. Dysregulation of such disease modules is best corrected by multitarget, synergistic network pharmacology. Here we test this principle in acute ischemic stroke, a highly unmet medical indication without any approved neuroprotective drug so far.
We extend 3 validated risk genes, neuronal nitric oxide synthase (), NADPH oxidase 5 (), and soluble guanylate cyclase (), to a single disease module. For preclinical validation, we used C57/Bl6 mice and humanized -knock-in mice because is not present in the mouse genome despite playing a key role in early stroke. Because up to 70% of patients with stroke have diabetes or prediabetes as an aggravating comorbidity, we also induced diabetes in these mice to model the increased clinical risk for hemorrhagic transformation.
We found that a triple-drug combination of a inhibitor, a nitric oxide synthase inhibitor, and an activator reduced infarct size and, in diabetic animals, also prevented hemorrhagic transformation. Reducing each individual compound dose to subthreshold levels still resulted in full protection when combined, typical for supra-additive network pharmacology. To examine clinical safety, 3 drugs, either marketed for or repurposed for nitric oxide synthase and NADPH oxidase, were administered to healthy volunteers in a phase I trial.
Our data establish that a mechanism-based network pharmacology approach is effective and clinically safe, warranting a currently ongoing first-in-class neuroprotective phase II interventional trial.
URL: https://clinicaltrials.gov/study/NCT05762146?term=repo-stroke&rank=1; Unique Identifier: NCT05762146.
除罕见和传染性疾病外，大多数人类疾病的定义是基于特定器官的症状，而非因果分子机制。这使得治疗局限于不精确的对症方法，所需治疗人数众多。相反，系统医学采用整体方法，基于相关风险基因、其编码的蛋白质以及蛋白质 - 蛋白质相互作用，以一种不依赖器官的方式定义疾病。此类疾病模块的失调最好通过多靶点、协同的网络药理学来纠正。在此，我们在急性缺血性卒中中验证这一原则，急性缺血性卒中是一种尚未得到充分满足的医学适应症，目前尚无任何获批的神经保护药物。
我们将3个经过验证的风险基因，即神经元型一氧化氮合酶（）、NADPH氧化酶5（）和可溶性鸟苷酸环化酶（）扩展为一个单一的疾病模块。为进行临床前验证，我们使用了C57/Bl6小鼠和人源化 - 敲入小鼠，因为尽管 在早期卒中中起关键作用，但小鼠基因组中不存在 。由于高达70%的卒中患者患有糖尿病或糖尿病前期作为加重的合并症，我们还在这些小鼠中诱导糖尿病，以模拟出血性转化增加的临床风险。
我们发现，一种 抑制剂、一种一氧化氮合酶抑制剂和一种 激活剂的三联药物组合可减小梗死体积，并且在糖尿病动物中还可预防出血性转化。当将每种单独化合物的剂量降至阈下水平时，联合使用仍可产生完全保护作用，这是超相加网络药理学的典型特征。为检查临床安全性，在一项I期试验中，将3种药物（要么是已上市用于 的药物，要么是重新用于一氧化氮合酶和NADPH氧化酶的药物）给予健康志愿者。
我们的数据表明，基于机制的网络药理学方法是有效且临床安全的，这为目前正在进行的同类首个神经保护II期干预试验提供了依据。
网址：https://clinicaltrials.gov/study/NCT05762146?term=repo - stroke&rank=1；唯一标识符：NCT05762146。
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