A Novel C5a-neutralizing Mirror-image (L-)Aptamer Prevents Organ Failure and Improves Survival in Experimental Sepsis

被引：74

作者：

Hoehlig, Kai ^{[1
]}

Maasch, Christian ^{[1
]}

Shushakova, Nelli ^{[2
]}

Buchner, Klaus ^{[1
]}

Huber-Lang, Markus ^{[3
]}

Purschke, Werner G. ^{[1
]}

Vater, Axel ^{[1
]}

Klussmann, Sven ^{[1
]}

机构：

[1] NOXXON Pharma AG, D-10589 Berlin, Germany

[2] Phenos GmbH, Hannover, Germany

[3] Univ Ulm, Ctr Surg, Dept Traumatol Hand Plast & Reconstruct Surg, D-89069 Ulm, Germany

来源：

MOLECULAR THERAPY | 2013年 / 21卷 / 12期

关键词：

INFLAMMATORY RESPONSE; INNATE IMMUNITY; COMPLEMENT; C5A; INHIBITION; RECEPTOR; RNA; ANAPHYLATOXIN; DYSFUNCTION; ACTIVATION;

D O I：

10.1038/mt.2013.178

中图分类号：

Q81 [生物工程学（生物技术）]; Q93 [微生物学];

学科分类号：

071005 [微生物学]; 090105 [作物生产系统与生态工程];

摘要：

Complement factor C5a is a potent proinflannmatory mediator that contributes to the pathogenesis of numerous inflammatory diseases. Here, we describe the discovery of NOX-D20, a PEGylated biostable mirror-image mixed (L-)RNA/DNA aptamer (Spiegelmer) that binds to mouse and human C5a with piconnolar affinity. In vitro, NOX-D20 inhibited C5a-induced chemotaxis of a CD88-expressing cell line and efficiently antagonized the activation of primary human polymorphonuclear leukocytes (PMN) by C5a. Binding of NOX-D20 to the C5a moiety of human C5 did not interfere with the formation of the terminal membrane attack complex (MAC). In sepsis, for which a specific interventional therapy is currently lacking, complement activation and elevated levels of C5a are suggested to contribute to multiorgan failure and mortality. In the model of polymicrobial sepsis induced by cecal ligation and puncture (CLP), NOX-D20 attenuated inflammation and organ damage, prevented the breakdown of the vascular endothelial barrier, and improved survival. Our study suggests NOX-D20 as a new therapeutic candidate for the treatment of sepsis.

引用

页码：2236 / 2246

页数：11

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