Development of a gene-eluting stent for the treatment of in-stent restenosis
Ganly, Sandra Maria
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In-stent restenosis (ISR) results from stent-induced arterial injury, characterized by a complex cascade of cellular and biochemical events. The removal of endothelium during an angioplasty procedure causes the underlying medial layer to change phenotype, thus inducing the formation of neointimal hyperplasia (NIH) in certain patient populations. It is proposed that promoting re-endothelialisation at a very early stage post-stenting could stimulate the exposed smooth muscle cell layer to return to a quiescent, non-proliferative state, thus preventing NIH formation. Drug-eluting stents (DES) have revolutionized the field of stenting and the treatment of ISR specifically. However, off-label use in contra-indicated patients, the incidence of late stent thrombosis (LST), and the necessity for the long-term administration of anti-platelet therapy hampers DES technology, and as a result, ISR continues to be a significant clinical complication for high-risk cardiovascular patients. Gene therapy approaches have recently emerged as a potential therapeutic strategy for the treatment of a variety of cardiovascular diseases. In the case of ISR, taking a gene therapy approach to stenting, which aims to repair and regenerate endothelium while preventing NIH formation, could be an attractive alternative to DES. The work presented in this thesis focused on the development of a Gene-eluting stent (GES) platform to safely and efficiently deliver a therapeutic gene to the vasculature to prevent the incidence of ISR post-stenting. This research is multi-disciplinary by nature, merging engineering, scientific and clinical principles and perspectives, to develop a proof-of-concept GES. A coronary stent, coated with a non-viral vector containing a therapeutic gene (eNOS), was successfully implanted in a hypercholesterolemic rabbit model. Successful transduction of the cells at the site of injury was achieved. Although, the hyperplasia mass of the in-stent lesions was not reduced, the re-establishment of a functioning endothelium was a significant result. Restoring the original, non-thrombogenic properties of this intimal layer is particularly noteworthy, as it is the thrombogenic nature of an exposed medial layer (caused by stent-induced arterial injury) that warrants the long-term administration of anti-platelet therapy, to prevent late stent thrombotic events, currently associated with DES.
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