Obstructed blood vessels can be operated on and adequate blood flow restored. However, stents and bypasses are often subject to high reclosure rates. Excessive immune reactions close to where the intervention took place might prevent the regeneration of adjacent vessel walls and even lead to reclosure. New interventions involving RNA interference seem to be a way out of this dilemma.
Cardiovascular diseases are the number one cause of death in Germany. According to the WHO, roughly 12 million people worldwide die of cardiovascular diseases every year. Controllable heart disease factors include excess weight, smoking and physical inactivity. Despite comprehensive information and prevention campaigns, the problem stands to increase among ageing Western populations. Constricted and obstructed blood vessels are the most common direct cause of cardiovascular diseases. Numerous treatment methods to restore adequate blood flow are now available, including sophisticated coronary artery bypass surgery. For bypass surgery, superficial veins are taken from the patient’s legs, inserted between the aorta and joined to a part of the artery below the obstructive lesion. Another possibility is the use of stents or artificial vascular grafts made of a polymer reinforced by a metal mesh. Less extensive vascular obstructions can be treated using a balloon dilatation catheter to inflate a peripheral blood vessel and improve the blood flow in the compromised artery. These interventions are usually carried out in combination with medicinal therapy and, together with a change in lifestyle, are directed towards restoring a normal blood flow.
However, it is still difficult to prevent new blockages, and bypass grafts can close again and fail due to a process known as restenosis. Numerous studies have been carried out to assess the risk of restenoses, and some studies have identified a frequency of 30 per cent and more. Coated drug-eluting stents that slowly release a drug to block cell proliferation have been on the market for quite some time. However, the so-called ideal stent is still lacking. A major cause of restenosis is the surgical intervention itself, which can lead to an excessive immune reaction in the treated area. Leukocytes attach to the vessel wall and mediate inflammatory processes that eventually lead to the reclosure of the artery.
Dr. Andrea Nolte, PD Dr. Tobias Walker and Prof. Dr. Hans Peter Wendel from the Department of Thoracic, Cardiac and Vascular Surgery (Medical Director: Prof. Dr. Dr. Schlensak) at the University Hospital of Tübingen have been focusing on these mechanisms for several years and hope to be able to prevent them from occurring by using innovative regenerative methods. In a BMBF-funded project carried out in cooperation with industrial partners and researchers from the NMI Natural and Medical Sciences Institute in Reutlingen, Nolte, Walker and Wendel have developed “gene-silencing stents”. These stents have been shown to improve the outcome of intravascular interventions. The implanted stents elute specific small interfering RNAs (siRNAs) that silence specific genes involved in inflammatory signalling cascades. The method does not lead to changes in the genome and the silencing effect is only transient. This is why this technique is not considered to be gene therapy.
The development of suitable siRNA was an important step on the researchers’ path towards developing a therapy that enabled better vascular wall regeneration. However, the researchers were faced with many more challenges. For example, they had to find a suitable transfection mechanism that enabled the functional and local delivery of double-stranded RNA into the cytosol of endothelial cells located in the vicinity of the stent. This was necessary as RNA is only enzymatically cleaved into smaller siRNA fragments inside cells. “Many means of transfection that are suitable for robust cancer cells such as HeLa cells kill endothelial cells and were therefore unsuitable for our purposes,” said Nolte. Another obstacle was the local administration of the siRNAs: “We were confronted with numerous technical difficulties. For example, we had to find a way to encapsulate the RNA in order to prevent it from being destroyed by the RNAse enzymes. We also had to find a solution that enabled us to immobilize the capsules with the polymer which we used to coat the stent.” And last not least, the researchers also had to deal with the release kinetics as the siRNA must only exert its effect for as long as the tissue is affected by the surgical intervention.
“The interaction of the siRNA with the components of the vascular wall proved to be the major challenge; we had to find the right combination of effect and compatibility,” said Wendel summarizing their research. This is now something the researchers have succeeded in doing. The BMBF project is drawing to a close and the researchers are specifically concentrating on validating the new technology. “One of our industrial partners is a stent manufacturer, and this company will be placing our “gene-silencing stents” on the market in the not-too-distant future,” said Wendel referring to the commercially relevant success of the project.
The researchers are nevertheless not sitting on their laurels and have plans to transfer the principle to other applications, for example the knock-down of genes that are upregulated under different pathological conditions. “We have plans to apply the encapsulated RNA to special medicinal products”, said Wendel who can even imagine applying the method to neuronal stents in the brain.
Further information:University Hospital of TübingenDepartment of Thoracic, Cardiac and Vascular SurgeryProf. Dr. Hans Peter Wendel (Research director)Calwerstr. 7/172076 TübingenTel.: +49 (0)7071/ 29 - 86 605E-mail: hans-peter.wendel(at)med.uni-tuebingen.de