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

这项小型企业创新研究（SBIR）第一阶段项目将开发一种新的方法来准确预测冠状动脉疾病（CAD）的风险。由于高密度脂蛋白（HDL）可以保护患者免受CAD的影响，目前评估风险的方法是测量HDL的胆固醇含量（HDL-C）作为HDL量的替代指标。然而，HDL的功能，即其排出胆固醇的能力，是降低CAD风险的原因。肥胖和糖尿病易患CAD并损害HDL胆固醇流出活性。由于直接定量的胆固醇流出活动是不服从临床实验室，我们开发了一种新的测定，使用电子顺磁共振（EPR）光谱间接报告HDL？的胆固醇流出活性。我们的分析在大约10分钟内对少于10 μl的血浆/血清进行，适用于常规自动化，高通量临床应用。目标是：1）与HDL胆固醇流出活性的直接测量相比，验证EPR测定，和2）确定我们的测定在已建立的2型糖尿病个体队列（METSIM）中鉴定功能障碍的HDL的预测能力。预计该测定将具有上级的灵敏度和预测能力，超过所有现有的方法来确定CAD risk.The更广泛的影响/商业潜力，该项目是能够快速评估HDL功能和准确预测CAD风险，一个数十亿美元的商业机会，在医疗诊断和药物开发空间。该项目将开发和验证一种快速，灵敏和准确的检测方法，报告HDL功能。这种创新的（一流的），不连续的（超越HDL-C）和转换的测定（直接在血浆中HDL功能的高度特异性测量）可用作诊断测定，以识别处于风险中的患者，即使是那些具有正常HDL-C水平的患者，并作为临床试验和患者管理中的替代结果测量。我们的检测试剂盒以不依赖于年龄和性别的方式作为代谢疾病状态的窗口的卓越能力是前所未有的。这项技术有望大大改善CAD和代谢性疾病易感性的早期诊断，促进预防疾病的干预措施的发现和实施，并显著降低长期医疗成本。更广泛地使用EPR光谱来测量蛋白质的结构变化作为疾病的功能性生物标志物，这代表了一个平台创新，标志着分子诊断的新时代。

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.