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

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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.