Fellowship in support of Neel Mansukhani "An Engineered Targeted Nanotherapy for Treatment of Atherosclerosis"

Atherosclerosis, the mechanism responsible for cardiovascular disease, is the leading cause of death and disability in the Unites States.1 Best medical therapy includes risk factor modification and treatment with high dose statin medications; however, on high dose statins there is still a 22% rate of death or major adverse cardiovascular events at 2 years.2 Thus, there is a great need to develop a novel therapy to prevent and treat atherosclerosis. The objective of this project is to develop an innovative technology that targets and treats atherosclerotic lesions. Specifically, we aim to engineer and evaluate a novel peptide amphiphile (PA) nanofiber that when administered intravenously is able to target sites of atherosclerotic lesions and deliver a therapeutic payload capable of inducing plaque stabilization and plaque regression. Our hypothesis is that systemic administration of a novel PA nanofiber will target atherosclerotic lesions, prevent the further development of atherosclerosis, and promote regression of pre-existing atherosclerotic plaques. To evaluate this hypothesis, we propose the following Specific Aims for this 1-year proposal: Aim 1 – To synthesize an Apolipoprotein A1 (ApoA1)-targeted nanofiber and evaluate its ability to bind to atherosclerotic plaques. Specifically, we will synthesize a PA nanofiber that contains an ApoA1 peptide sequence to target the nanofiber to atherosclerotic lesions. We will evaluate the ability of this ApoA1-targeted PA nanofiber to bind to atherosclerotic lesions using LDL receptor knockout (LDLR KO) mice fed a high fat diet. Variables to be assessed include binding duration and specificity. Aim 2 – To incorporate a therapeutic agent into the ApoA1-targeted nanofiber to evaluate the ability of this nanofiber to prevent development of new, and promote regression of pre-existing atherosclerotic plaques. Specifically, we will incorporate an LXR agonist into the ApoA1-targeted nanofiber and evaluate the ability of this nanofiber to prevent development of new, and promote regression of pre-existing atherosclerotic lesions using LDLR KO mice fed a high fat diet. Successful completion of these innovative studies will result in the development of a paradigm-shifting technology, as no such targeted therapy exists in the vascular arena.