Controllable, local release of synthetic messenger RNA for recovery of the vessel wall

合成信使 RNA 的可控局部释放，用于血管壁的恢复

• 批准号: 250926193
• 负责人: Professorin Dr. Stefanie Krajewski
• 金额: --
• 依托单位: Klinisches Forschungslabor
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2014
• 资助国家: 德国
• 起止时间: 2013-12-31 至 2017-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/250926193?language=en
• 关键词: Controllable; local; release; synthetic; messenger

Until today, narrowing of the arteries, also described as atherosclerosis, is one of the most common chronic diseases, which can, in the worst case of total vessel occlusion, result in heart attack or stroke. Next to bypass surgery, where the narrowed blood vessel is replaced, angioplasty is routinely performed. Thereby, narrowed or already occluded arteries are reopened via minimally invasive implantation of a so-called stent in order to support the blood vessel. However, in spite of tremendous progress regarding stent design, stent surface modification and the use of drug-eluting stents (DES), two fundamental problems occur, which can not be completely avoided so far: 1) the artificial surface, the drugs used in DES as well as the destroyed endothelium caused through stent implantation induce activation of platelets, which can lead to life-threatening thrombotic complications; 2) there is always a risk of renarrowing of the blood vessel (restenosis) caused by increased proliferation of smooth muscle cells into the lumen. Due to these reasons, patients need to be put under medication for several months or as a worst case scenario undergo another surgery. The aim of this project is to generate an effective, bioactive coating for stents in order to inhibit platelet activation as well as proliferation of smooth muscle cells after stent angioplasty. Therefore, the characteristics of the ATP- and ADP-hydrolyzing enzyme CD39 will be used, as these nucleotides play a key role in platelet activation as well as in proliferation of smooth muscle cells. Consequently, human CD39 protein as well as CD39 messenger RNA (mRNA) will be produced in the first part of the project. Coating of stents with CD39 protein will lead to direct hydrolysis of ATP and ADP after stent implantation, which particularly results in inhibition of ADP-mediated platelet activation and consequent thrombotic complications. On the other hand simultaneous coating with CD39 mRNA will induce CD39 protein overexpression in endothelial cells after local release of mRNA from the stent allowing specific control of physiological CD39 expression. Next to inhibition of platelet activation, such a stent would support the integrity of the endothelium and inhibit proliferation of smooth muscle cells caused by extracellular nucleotides.Overall, the project presents a completely innovative and promising therapy concept to treat atherosclerosis in any kind of blood vessels by reducing the risk of stent angioplasty-associated complications and thereby increasing the safety of patients.

直到今天，动脉狭窄，也被称为动脉粥样硬化，是最常见的慢性疾病之一，在最坏的情况下，完全血管闭塞，导致心脏病发作或中风。接下来的搭桥手术，狭窄的血管被替换，血管成形术是例行进行。因此，狭窄或已经闭塞的动脉通过所谓的支架的微创植入而重新开放，以便支撑血管。然而，尽管在支架设计、支架表面改性和药物洗脱支架（DES）的使用方面取得了巨大的进步，但仍存在两个无法完全避免的基本问题：1）人工表面、DES中使用的药物以及支架植入引起的内皮破坏诱导血小板活化，这可导致危及生命的血栓性并发症; 2）总是存在由平滑肌细胞向管腔中的增殖增加引起的血管再狭窄（再狭窄）的风险。由于这些原因，患者需要接受数月的药物治疗，或者在最坏的情况下接受另一次手术。该项目的目的是为支架产生有效的生物活性涂层，以抑制血小板活化以及支架血管成形术后平滑肌细胞的增殖。因此，将使用ATP和ADP水解酶CD 39的特性，因为这些核苷酸在血小板活化以及平滑肌细胞增殖中起关键作用。因此，人类CD 39蛋白以及CD 39信使RNA（mRNA）将在该项目的第一部分产生。用CD 39蛋白涂覆支架将导致支架植入后ATP和ADP的直接水解，这特别导致ADP介导的血小板活化的抑制和随后的血栓形成并发症。另一方面，同时用CD 39 mRNA包被将在mRNA从支架局部释放后诱导内皮细胞中的CD 39蛋白过表达，从而允许特异性控制生理性CD 39表达。除了抑制血小板活化外，这种支架还可以支持内皮的完整性，抑制细胞外核苷酸引起的平滑肌细胞增殖。总的来说，该项目提出了一个完全创新和有前途的治疗概念，通过降低支架血管成形术相关并发症的风险来治疗任何类型血管中的动脉粥样硬化，从而提高患者的安全性。