BACKGROUND:  Commonly known as "hardening" of the arteries, atherosclerosis is a disease characterized by chronic inflammatory response in the blood vessel wall. The atherosclerotic lesion formation is caused by a variety of factors, including oxidized lipids and lipoproteins, cytokines, and chemokines. Atherosclerosis is considered the most important underlying cause of strokes, heart attacks, and various cardiovascular diseases. The most common symptom for atherosclerosis is angina (i.e. heart pain), although an individual can be asymptomatic for a number of years before the first clinical incident or heart attack. The plaques that form from atherosclerosis will eventually lead to stenosis (i.e. blockage of the blood vessel), thus leading to reduced blood supply to target organs. Although statins have caused a significant improvement in the treatment of atherosclerosis and its complications, still a large number of heart attacks and strokes result in morbidity and mortality in the aging population. Better understanding of the molecular signaling pathways involved in the pathogenesis of atherosclerosis will identify novel targets for intervention with this deadly disorder.

INNOVATION:  The present invention describes a method by which hedgehog pathway modulators are used for the therapeutic intervention of atherosclerosis and other cardiovascular diseases. Based on the novel evidence presented here suggesting that hedgehog signaling is highly activated in atherosclerostic lesions of mice and humans, as well as in artery wall cells treated with inflammatory molecules, the investigators suggest that regulation of such aberrant hedgehog signaling in the artery wall will present novel opportunities for prevention and/or treatment of atherosclerosis and other chronic inflammatory diseases.

POTENTIAL APPLICATIONS:  Modulation of the hedgehog pathway through pharmaceutical compounds targeted at vascular cells and/or immune cells and the blood vessel wall.

ADVANTAGES

• Exploits a novel molecular mechanism behind the formation of atherosclerotic plaques.
• Can be targeted to the vascular or immune cells involved in the pathogenesis of atherosclerosis.
• Targets a highly druggable pathway that also underlies several cancers that are caused by aberrant hedgehog signaling. Such antagonists of hedgehog signaling for targeting human tumors are already under development by a number of biotechnology and pharmaceutical companies.

DEVELOPMENT-TO-DATE:  The invention has been developed conceptually and has been tested in vitro and in vivo to demonstrate the activation of hedgehog signaling in the context of atherosclerosis and vascular calcification. Candidate compounds have been identified through previous efforts by the investigators.

Reference: UCLA Case No. 2007-452