Translating Lp(a) biology to clinical applications

该提案旨在产生新的、广泛可用的试剂和方法，以改善生物样品的性质。 测量Lp（a）水平以改善患者护理。Lp（a）水平升高非常普遍， 通常被认为是CVD的独立、遗传和可能的因果风险因素。Lp（a）水平 在临床实验室中测量，它是最难准确测量的实验室分析物之一 这是因为它具有多个相同的Kringle重复序列的独特结构。重要的技术和 方法学上的差距限制了Lp（a）测量在临床实验室和 临床水平。主要的局限性是缺乏广泛可用的、全球标准化的诊断方法， 方法，特别是单克隆抗体，仅结合一次Lp（a），可用于准确地 定量Lp（a）。这种缺乏标准化的情况可能会通过错误分配Lp（a）风险而产生不良的临床后遗症 阈值或治疗目标。由于上述限制，FDA尚未批准任何Lp（a） 以摩尔浓度测定。NHLBI Lp（a）工作组于2017年和2019年举办了两次研讨会 并建议所有利益攸关方开展建设性合作，以确保标准化， 协调Lp（a）测定法，并开发使用单克隆抗体的亚型独立测定法 对载脂蛋白（a）上的一个位点具有特异性的抗体。为了解决这些差距，在照顾病人的提高， Lp（a），我们提出了以下具体目标：1-开发和验证亚型独立的Lp（a）测定 与最近产生的亚型非依赖性单克隆抗体; 2-产生第二种亚型- 独立的单克隆抗体，以促进开发第一个亚型独立的非ELISA 方法适用于医院和商业实验室。我们将与CDC/IFCC合作， 在临床实验室界面验证这种新的ELISA;以及3-将这些新的测定法应用于临床 人类疾病的可翻译性数据集，包括种族/民族差异研究，反义Lp（a）- 降低治疗和CVD结果研究。

This proposal intends to generate novel, widely available reagents and methods to Improve the measurement of Lp(a) levels in order to improve patient care. Elevated Lp(a) levels are highly prevalent and generally accepted as an independent, genetic and likely causal risk factor for CVD. Although Lp(a) levels are measured in clinical laboratories, it is one of the most difficult laboratory analytes to measure accurately because of its unique structure of multiple, identical kringle repeats. Significant technological and methodological gaps exist that limit the accuracy of Lp(a) measurements at the both the clinical laboratory and clinical level. The major limitation is the lack of widely available, globally standardized, diagnostic methods, and specifically monoclonal antibodies that bind only once to Lp(a) that can be used to accurately quantitate Lp(a). This lack of standardization may have adverse clinical sequalae by mis-assigning Lp(a) risk thresholds or targets for therapy. Due to the limitations noted above, the FDA has yet to approve any Lp(a) assay in molar concentration. The NHLBI Working Group on Lp(a) organized 2 workshops in 2017 and 2019 and recommended constructive collaboration among all stakeholders to ensure standardization and harmonization of Lp(a) assays and to develop assays that are isoform independent using monoclonal antibodies that are specific to one site on apo(a). To address these gaps in the care of patients with elevated Lp(a), we propose the following specific aims: 1- to develop and validate an isoform independent Lp(a) assay with a recently generated isoform-independent, monoclonal antibody; 2- to generate a second, isoform- independent, monoclonal antibody to facilitate the development of a first, isoform-independent non-ELISA methodology adaptable to hospitals and commercial laboratories. We will collaborate with the CDC/IFCC to validate this new ELISA at the clinical laboratory interface; and 3- to apply these novel assays to clinical datasets for translatability to human disease, including studies of racial/ethnic differences, antisense Lp(a)- lowering therapy and in CVD outcome studies.