Cardiovascular disease (CVD) is the leading cause of death worldwide. Despite the major technological advances in stent therapy over the past two decades, restenosis and thrombosis (primarily late and very late) remain principal factors contributing to stent-associated morbidity and mortality rates. To date, stent therapies are non-selective, affecting vascular smooth muscle cells and endothelial cells alike and exacting unfavorable trade-offs. Drug-eluting stents (DES) effectively suppress neointimal growth, but at the expense of poor stent strut coverage with incompetent endothelium. This inability to deliver cell-selective therapy has hindered progress in percutaneous interventions. In response, we have developed an innovative microRNA (miRNA)- based, cell-selective therapy that achieved striking results in an established normal rat model of balloon angioplasty. This novel therapy selectively inhibited neointimal hyperplasia and inflammation while simultaneously promoting vessel reendothelialization, reducing hypercoagulability and restoring the endothelium-dependent vasodilatory response to levels indistinguishable from uninjured control. To translate this therapeutic strategy to a clinical setting, and better reflect the condition of patients that undero interventional procedures, we aim to test the efficacy of our strategy in a rabbit model of established atherosclerosis. In three specific aims, we will evaluate the ability of this miRNA-based, cell-selective therapy to (1) inhibit atherogenesis; (2) promote atheroregression; and (3) inhibit in-stent restenosis and restore endothelial-strut coverage when compared against DES. These studies have tremendous therapeutic implications, and their successful completion will advance the development of cell-selective therapies and significantly impact the clinical practice of cardiovascular intervention to improve the life expectancy of CVD patients.

Public Health Relevance

Despite major technological advances in stent therapy over the past two decades for the treatment of cardiovascular diseases, restenosis and thrombosis remain the principal factors contributing to stent- associated morbidity and mortality. To improve upon current stent technologies, we have developed a microRNA-based, cell-selective therapy to selectively inhibit vascular smooth muscle cell hyperplasia and inflammation following percutaneous interventions without affecting competent vessel reendothelialization. We will test the efficacy of our strategy in a rabbit model of established atherosclerosis to best reflect the condition of atherosclerotic patients and predict the human clinical outcome of our therapy.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL128411-03
Application #
9268806
Study Section
Gene and Drug Delivery Systems Study Section (GDD)
Program Officer
Olive, Michelle
Project Start
2015-07-15
Project End
2020-04-30
Budget Start
2017-05-01
Budget End
2018-04-30
Support Year
3
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of South Florida
Department
Physiology
Type
Schools of Medicine
DUNS #
069687242
City
Tampa
State
FL
Country
United States
Zip Code
33612
Mong, Ezinne Francess; Akat, Kemal Marc; Canfield, John et al. (2018) Modulation of LIN28B/Let-7 Signaling by Propranolol Contributes to Infantile Hemangioma Involution. Arterioscler Thromb Vasc Biol 38:1321-1332
Totary-Jain, Hana; Sionov, Ronit Vogt; Gallily, Ruth (2016) Indomethacin sensitizes resistant transformed cells to macrophage cytotoxicity. Immunol Lett 176:1-7