Research Project
8906059
? DESCRIPTION (provided by applicant):: Navidea Biopharmaceuticals is seeking support to progress efforts designed ultimately to determine if its diagnostic imaging agent, 99mTc-tilmanocept, can be used to improve upon the identification of atherosclerotic plaques that are at high-risk for near term rupture. High-risk atherosclerotic plaques are referred to as vulnerable plaques or thin cap fibroatheromas (TCFA). Rupture of a TCFA causes thrombus (blood clot) formation leading to blockage of arterial blood flow. Such ruptures are the leading cause of myocardial infarctions (heart attacks) and sudden cardiac death. Such TCFA ruptures also contribute significantly to the incidence of strokes. Atherosclerosis is a chronic and progressive inflammatory syndrome that develops slowly over the course of many years or decades to generate atherosclerotic plaques in the walls of arteries. Individuals infected with HIV experience much accelerated rates of atherosclerosis development even if they are being successfully treated with antiretroviral therapies. Generally, atherosclerosis is asymptomatic until a TCFA ruptures and the patient experiences a potentially catastrophic cardiovascular disease (CVD) event. A large portion of the population has atherosclerotic plaques to some degree. Most of these plaques are stable and are relatively unlikely to precipitate a major CVD event. In this application, Navidea and its collaborators (Dr. Steven Grinspoon et al) at Massachusetts General Hospital are addressing the need for a more efficacious means to identify TCFA and differentiate TCFA from stable atherosclerotic plaques in cardiovascular imaging studies. The potential public health benefit of this project is that asymptomatic persons with high-risk TCFA could be placed on currently available therapies which will significantly lower their chances of experiencing a TCFA rupture and a major and potentially life threatening CVD event. Many lives may be saved, and the lives of many patients could be greatly improved. 99mTc- Tilmanocept was purposely designed to bind to the macrophage mannose receptor (CD206). CD206 expressing macrophages populate tumor associated lymph nodes, facilitating accumulation and retention of 99mTc-tilmanocept in SLN. Recently, it has been observed that CD206 expressing macrophages densely populate TCFA but not other kinds (i.e. stable) atherosclerotic plaques. Thus, patients injected with 99mTc- tilmanocept may accumulate this imaging agent specifically in TCFA should they occur. Visualization of retained 99mTc-tilmanocept in TCFA may possible with SPECT/CT, thereby, identifying patients at high-risk for near term CVD events. The proposed study has two specific aims. The first involved an examination of plaque tissue from both HIV infested and uninfected individuals to confirm the infiltration of CD206 expressing macrophages specifically in TCFA. The second specific aim involves a limited RDRC approved clinical study of 12 individuals with & without aortic atherosclerotic plaques and with & without HIV infections. This study will provide needed information about the feasibility of 99mTc-tilmanocept to better identify patients with TCFA.
