Grant: Project Grant

Despite enormous advances in prevention, diagnosis and management over the past few decades, heart disease remains the leading cause of death and disability in western societies. This disease burden translates into a huge cost to healthcare systems, which could be curbed if better approaches for treatment were developed. This proposal aims to develop a multifunctional gene delivery vehicle that can be administered non-locally for treatment of atherosclerosis. Current treatments involve revascularization procedures or the use of drugs, which require frequent dosing and are associated with untoward side effects such as toxicity, development of resistance, and off-target effects. Conversely, gene therapy has always had high potential but its translation to the clinic has been slow, mainly due to unpredictable and unsafe viruses as gene carriers. To date, there is no report involving non-viral nanotechnology to provide gene-based therapies for atherosclerosis. We propose a synthetic polymer-based nanocarrier to deliver anti-inflammatory genes directly to the disease site to slow atherosclerotic progression and stabilize fatty plaques. The main features of the proposed delivery vehicle include a biodegradable and biocompatible polymer and bioconjugated targeting peptides capable of localizing preferentially to the disease site. Our preliminary results showed that the multifunctional nanoplex is non-toxic, able to deliver anti-inflammatory genes with high efficiency, and able to attenuate inflammation in vitro. As such, the proposed non-viral and anti-inflammatory gene therapy strategy would be the first of its kind to address the underlying driver of atherosclerotic plaque formation, non-resolving inflammation. The project would contribute to advancing the knowledge of cardiovascular disease progression and could also be envisioned for other chronic inflammatory diseases such as Crohn's, arthritis, and multiple sclerosis.