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

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，在最严重的血管完全闭塞的情况下，可能会导致心脏病发作或中风。除了搭桥手术，狭窄的血管被替换，血管成形术也是常规操作。因此，狭窄或已经闭塞的动脉通过微创植入所谓的支架来重新开放，以支持血管。然而，尽管支架设计、支架表面改性和药物洗脱支架(DES)的使用取得了巨大进展，但仍然存在两个到目前为止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置入时破坏的内皮会诱导血小板激活，从而导致危及生命的血栓并发症；2)由于血管内平滑肌细胞增殖增加而导致血管再狭窄的风险总是存在的。由于这些原因，患者需要接受几个月的药物治疗，或者在最糟糕的情况下接受另一次手术。该项目的目的是为支架提供一种有效的生物活性涂层，以抑制支架血管成形术后的血小板活化和平滑肌细胞的增殖。因此，将使用ATP和ADP水解酶CD39的特性，因为这些核苷酸在血小板激活和平滑肌细胞增殖中发挥关键作用。因此，该项目的第一部分将生产人CD39蛋白和CD39信使RNA(MRNA)。CD39蛋白包被支架后会导致支架内ATP和ADP的直接水解，特别是抑制ADP介导的血小板活化，从而导致血栓并发症。另一方面，支架局部释放出CD39基因后，同时包裹CD39基因，可诱导内皮细胞CD39蛋白过度表达，从而实现对生理CD39基因表达的特异性调控。除了抑制血小板活化，这种支架还将支持内皮的完整性，并抑制细胞外核苷酸引起的平滑肌细胞的增殖。总体而言，该项目提出了一种全新的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，治疗任何类型的血管的动脉粥样硬化，从而提高患者的安全性。

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.