利用液体活检的个体化蛋白质组学进行治疗药物的再定位。
Therapeutic drug repositioning using personalized proteomics of liquid biopsies.
机构信息
Omics Laboratory, Stanford University, Palo Alto, California, USA.
Department of Ophthalmology, Byers Eye Institute, Stanford University, Palo Alto, California, USA.
出版信息
JCI Insight. 2017 Dec 21;2(24):97818. doi: 10.1172/jci.insight.97818.
BACKGROUND
In patients with limited response to conventional therapeutics, repositioning of already approved drugs can bring new, more effective options. Current drug repositioning methods, however, frequently rely on retrospective computational analyses and genetic testing - time consuming methods that delay application of repositioned drugs. Here, we show how proteomic analysis of liquid biopsies successfully guided treatment of neovascular inflammatory vitreoretinopathy (NIV), an inherited autoinflammatory disease with otherwise poor clinical outcomes.
METHODS
Vitreous biopsies from NIV patients were profiled by an antibody array for expression of 200 cytokine-signaling proteins. Non-NIV controls were compared with NIV samples from various stages of disease progression. Patterns were identified by 1-way ANOVA, hierarchical clustering, and pathway analysis. Subjects treated with repositioned therapies were followed longitudinally.
RESULTS
Proteomic profiles revealed molecular pathways in NIV pathologies and implicated superior and inferior targets for therapy. Anti-VEGF injections resolved vitreous hemorrhages without the need for vitrectomy surgery. Methotrexate injections reversed inflammatory cell reactions without the side effects of corticosteroids. Anti-IL-6 therapy prevented recurrent fibrosis and retinal detachment where all prior antiinflammatory interventions had failed. The cytokine array also showed that TNF-α levels were normal and that corticosteroid-sensitive pathways were absent in fibrotic NIV, helping explain prior failure of these conventional therapeutic approaches.
CONCLUSIONS
Personalized proteomics can uncover highly personalized therapies for autoinflammatory disease that can be timed with specific pathologic activities. This precision medicine strategy can also help prevent delivery of ineffective drugs. Importantly, proteomic profiling of liquid biopsies offers an endpoint analysis that can directly guide treatment using available drugs.
背景
在对常规疗法反应有限的患者中，重新定位已批准的药物可以带来新的、更有效的选择。然而，当前的药物重定位方法经常依赖于回顾性的计算分析和基因测试，这些方法耗时，延迟了重定位药物的应用。在这里，我们展示了如何通过对液体活检的蛋白质组学分析成功指导新生血管性炎症性玻璃体视网膜病变（NIV）的治疗，这是一种遗传性自身炎症性疾病，临床预后较差。
方法
通过抗体阵列对 NIV 患者的玻璃体活检进行了 200 种细胞因子信号蛋白的表达谱分析。将非 NIV 对照与 NIV 患者在疾病进展的不同阶段的样本进行比较。通过单向方差分析、层次聚类和途径分析来识别模式。接受重新定位治疗的患者进行了纵向随访。
结果
蛋白质组学分析揭示了 NIV 病变中的分子途径，并暗示了治疗的优势和劣势靶点。抗血管内皮生长因子（VEGF）注射可解决玻璃体出血，无需玻璃体切除术。甲氨蝶呤注射可逆转炎症细胞反应，而无皮质类固醇的副作用。抗白细胞介素-6（IL-6）治疗可防止复发性纤维化和视网膜脱离，而所有先前的抗炎干预均失败。细胞因子阵列还表明，TNF-α 水平正常，纤维化 NIV 中缺乏皮质类固醇敏感途径，这有助于解释先前这些常规治疗方法失败的原因。
结论
个性化蛋白质组学可以为自身炎症性疾病揭示高度个性化的治疗方法，并且可以与特定的病理活动时间相匹配。这种精准医学策略还可以帮助避免无效药物的应用。重要的是，液体活检的蛋白质组学分析提供了一个终点分析，可以直接指导使用现有药物的治疗。
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