Development of a novel site-and cell-selective mRNA therapeutic to treat atherosclerosis

PROJECT SUMMARY Atherosclerotic cardiovascular diseases (ASCVDs) are the leading cause of death in the United States and worldwide. Atherosclerosis of the arteries underlies these conditions and is characterized by chronic inflammation and inappropriate proliferation of disease contributing cells. Current medications available for the treatment of atherosclerosis merely target risk factors, not the disease-causing cells themselves. Additionally, invasive procedures such as percutaneous coronary intervention (PCI) treat arterial stenosis but can have adverse effects such as thrombosis. Therefore, despite progress in the field, site-specific and cell-selective therapies that target the cells that form atherosclerotic plaques while sparing the vascular endothelium are not available. Thus, the main objective of this research proposal is to test the feasibility of a novel messenger RNA (mRNA) therapeutic that is site-specific in targeting regions of atherosclerotic plaques only, while specifically targeting disease causing cells, reducing inflammation, and sparing the vascular endothelium. This research is highly significant to public health as ASCVDs represent a major public health issue and place an enormous burden on our Nation. I hypothesize that a combination of microRNA (miRNA) switch and small interfering RNA (siRNA) technology into a single mRNA construct will allow for a first of its kind RNA therapeutic strategy to cause atherosclerotic plaque regression and resolution. In order to test the efficacy of this new therapeutic, I will employ a series of rigorous experiments using in vitro, in vivo, and ex vivo models. Importantly, my ex vivo model uses freshly isolated coronary arteries from human hearts, giving more clinical relevance to my work and allowing me to test my therapeutic on human arteries burdened with atherosclerotic plaques. We aim to make a positive impact on the field by not only designing a novel mRNA therapeutic to treat atherosclerosis, but also, by providing evidence for the effectiveness of this unique therapeutic strategy that can be modified in order to treat other diseases. I will work towards this goal under the mentorship of my sponsor, Dr. Hana Totary-Jain, an expert in the field of CVD as well as RNA therapeutic research, at the supportive research environment of USF Health’s Morsani College of Medicine. My mentor, committee, additional advisors, and department will provide me with all the necessary training and resources needed to complete this very impactful research while also preparing me for my next career stage as a post-doctoral scholar and eventually a principal investigator.