Internal Medicine, University of Iowa, Iowa City, IA, 52242, USA.
Molecular & Cellular Biology Program, University of Iowa, Iowa City, IA, 52242, USA.
Nat Commun. 2019 Jan 10;10(1):116. doi: 10.1038/s41467-018-08030-y.
The development of multiple organ dysfunction syndrome (MODS) following infection or tissue injury is associated with increased patient morbidity and mortality. Extensive cellular injury results in the release of nuclear proteins, of which histones are the most abundant, into the circulation. Circulating histones are implicated as essential mediators of MODS. Available anti-histone therapies have failed in clinical trials due to off-target effects such as bleeding and toxicity. Here, we describe a therapeutic strategy for MODS based on the neutralization of histones by chemically stabilized nucleic acid bio-drugs (aptamers). Systematic evolution of ligands by exponential enrichment technology identified aptamers that selectively bind those histones responsible for MODS and do not bind to serum proteins. We demonstrate the efficacy of histone-specific aptamers in human cells and in a murine model of MODS. These aptamers could have a significant therapeutic benefit in the treatment of multiple diverse clinical conditions associated with MODS.
感染或组织损伤后多器官功能障碍综合征（MODS）的发展与患者发病率和死亡率的增加有关。广泛的细胞损伤导致核蛋白释放到循环中，其中组蛋白最为丰富。循环组蛋白被认为是 MODS 的重要介质。由于出血和毒性等脱靶效应，现有的抗组蛋白疗法在临床试验中失败。在这里，我们描述了一种基于化学稳定核酸生物药物（适体）中和组蛋白的 MODS 治疗策略。通过指数富集配体系统进化技术，鉴定出了选择性结合导致 MODS 的组蛋白而不结合血清蛋白的适体。我们在人细胞和 MODS 小鼠模型中证明了组蛋白特异性适体的功效。这些适体在治疗与 MODS 相关的多种不同临床病症方面可能具有显著的治疗益处。
