Long-term clinical results of vessels treated with coronary stents show that restenosis still occurs frequently. Despite enormous progress in stent design, stent surfaces and the use of drug-eluting stents, the overall incompatibility of the implant with the vessel wall cells is too high.
The project aims to prevent leukocyte-endothelial cell adhesion, a key mechanism of restenosis. This will be achieved by temporally and spatially restricted specific reduction of the surface receptors ICAM1, VCAM1, and E-selectin on endothelial cells using RNAi-based specific receptor knockdown. The siRNA envisaged in the project already showed very good receptor knock-down results in vitro.
For therapeutic success, continuous RNAi transfection of endothelial cells in vivo for several weeks is additionally required. To achieve this goal, cell-compatible, controllable drug transporters have to be developed. These will simultaneously serve to stabilize RNA in blood and improve transfection efficiency, i.e., RNA uptake and action in cells.
In addition, the project calls for the first development of a coronary stent that can prevent the development of restenosis by controlled release of stabilized, complexed RNA over several weeks. This approach would be more effective and gentle than currently used therapies.
- To optimize all of these steps, the project has been divided into technological areas for simultaneous optimization by the project partners:
In the area of stent design, stents with the largest possible surface areas and gentle processes for crimping the coated stents onto the carrier balloons are being developed by Qualimed.
- In the area of transfection, CureVac is designing RNA nanoparticles with optimal particle size and surface charge and developing new approaches for RNA release in cells.
- Layer systems and hydrogels degradable after different times for stable coating of stents and for uptake and time-controlled delivery of high concentrations of RNA transfection particles are being established at the NMI.
The combination of individually optimized modules should enable rapid establishment of the RNA stent as a product. The knowledge gained from the optimization of the individual modules should also enable the rapid adaptation of the RNA stent assembly to therapeutic requirements.
- For this purpose, suitable model systems, as close as possible to the application, will be established at the UKT to test the therapeutic effect.
Summary: In the course of the project, new stent designs could be investigated and first functional models could be produced. By reducing surface charges, the aggregation of the RNA nanoparticles could be strongly reduced and the uptake into the cell improved. While maintaining the stability of the RNA nanoplexes, the release of RNA into cells could be significantly improved, thereby increasing the transfection efficiency in endothelial cells. Different layer systems for immobilization and time-controlled release of RNA nanoplexes could be established. Analytical methods for the measurement of layer formation and degradation were established.
- QualiMed Innovative Medizinprodukte GmbH
- CureVac GmbH
- Universitätsklinikum Tübingen