Research Project
6140064
Atherosclerosis and its subsequent complications, which include both stroke and heart attacks, remain the leading causes of morbidity and mortality in the United States and most westernized societies. Centaur proprietary compounds, NRTs, are efficacious in pilot atherosclerosis in vitro models. The experiments proposed focus on two objectives. The first objective is to identify NRTs for testing in long-term atherosclerosis rodent models. The capacity of NRTs to prevent surface adhesion molecule (ICAM-1) expression will be measured using human endothelial cells following ischemia/reoxygenation. NRTs will be evaluated for their ability to prevent monocyte chemoattractant protein-1 (MCP-1) release from human vascular smooth muscle cells challenged with either IL-1beta or TNFalpha. Active compounds will be further evaluated for safety using an acute toxicity screen in mice. The second objective will be to finish analyzing tissue from a study wherein NRTs were administered for 17 weeks to apolipoprotein-E-deficient (ApoE-/-) mice. Preliminary data show the ApoE-/- mice had elevated serum MCP- 1 levels and lesions were found on the intimal surface of the aorta. Both aortic root analysis and intimal surface lesion analyses are proposed. These studies set the stage for Phase II evaluations to identify an NRT for clinical evaluation as a therapeutic for atherosclerosis. PROPOSED COMMERCIAL APPLICATIONS: Atherosclerosis is a common disorder of the arteries in which fat, cholesterol and other substances collect in the walls of the arteries. Atherosclerosis and its subsequent complications, which include both stroke and heart attacks, remain the leading causes of morbidity and mortality in both men and women of all racial groups in the United States and most westernized societies. Atherosclerosis is a progressive disease but shows no symptoms until a complication occurs. Medications to date have focused on reducing blood fat or cholesterol (e.g., cholestyramine, colestipol, nicotinic acid genfibrozil, probucol, or lovastatin) or by reducing the risk of clot formation (e.g., aspirin and anticoagulants). Any therapeutic that could limit atherosclerotic damage would have widespread medical and commercial appeal. The market value of a safe therapeutic for atherosclerosis treatment is in the multi-billion dollar range. Centaur has NRTs that may be efficacious in pilot atherosclerosis models and are also extremely safe. Given their wide margin of safety and efficacy against numerous factors that influence inflammation, these compounds have a high probability of success to become atherosclerosis therapeutics.
