SBIR Phase I: Development and Validation of an In Vitro Diagnostic of HDL Cholesterol Efflux and Coronary Artery Disease Risk

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This Small Business Innovation Research (SBIR) Phase I project will develop a new approach to accurately predict coronary artery disease (CAD) risk. Because high-density-lipoprotein (HDL) protects from CAD, current methods to assess risk measure the cholesterol content of HDL (HDL-C) as a surrogate indicator of HDL quantity. However, the function of HDL, namely its ability to efflux cholesterol, is what reduces CAD risk. Obesity and diabetes predispose to CAD and compromise HDL cholesterol efflux activity. Because direct quantification of cholesterol efflux activity is not amenable to clinical laboratories, we developed a novel assay that uses electron paramagnetic resonance (EPR) spectroscopy to report indirectly on HDL?s cholesterol efflux activity. Our assay is performed in approximately 10 minutes on less than 10 µl of blood plasma/serum and is suitable for routine automated, high throughput clinical use. The objectives are: 1) validate the EPR assay compared to direct measurement of HDL cholesterol efflux activity, and 2) determine the predictive power of our assay to identify dysfunctional HDL in an established cohort of individuals with type 2 diabetes (METSIM). It is expected that this assay will have superior sensitivity and predictive power over all existing methods to determine CAD risk.The broader impact/commercial potential of this project is to enable rapid assessment of HDL function and accurately predict CAD risk, a multi-billion-dollar commercial opportunity in the medical diagnostics and drug development space. This project will develop and validate a rapid, sensitive and accurate assay that reports on HDL function. This innovative (first-in-class), discontinuous (goes beyond HDL-C), and transformational assay (highly specific measurement of HDL function directly in plasma) can be used as a diagnostic assay to identify patients at risk, even those with normal HDL-C levels, and as a surrogate outcome measure in clinical trials and patient management. The exceptional capability of our assay to serve as a window on metabolic disease status in an age- and gender-independent fashion is unprecedented. This technology promises to greatly improve the early diagnosis of CAD and metabolic disease predisposition and facilitate the discovery and implementation of interventions to prevent disease and significantly reduce long-term healthcare costs. The still broader use of EPR spectroscopy to measure structural changes in proteins as functional biomarkers of disease represents a platform innovation that denotes a new era of sophistication for molecular diagnostics.