Translating Lp(a) biology to clinical applications

将 Lp(a) 生物学转化为临床应用

• 批准号: 10593157
• 负责人: SOTIRIOS TSIMIKAS
• 金额: $ 62.77万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10593157
• 关键词: Address; Aortic Valve Stenosis; Awareness; Binding; Biological; Biological Assay; Biology; Carbohydrates; Cardiovascular Diseases; Centers for Disease Control and Prevention (U.S.); Cholesterol; Cholesterol Esters; Clinical; Clinical Chemistry; Clinical Data; Collaborations; Data Reporting; Data Set; Development; Diagnostic; Diagnostic Procedure; Educational workshop; Ensure; Enzyme-Linked Immunosorbent Assay; Generations; Genetic; Grant; Hospitals; Immunoassay; Incidence; Individual; International; International System of Units; Kringles; Laboratories; Latex Bead; Lipoprotein (a); Manufacturer; Mass Spectrum Analysis; Measurement; Measures; Methodology; Methods; Monoclonal Antibodies; National Heart, Lung, and Blood Institute; Outcome Study; Patient Care; Patients; Peptides; Phospholipids; Population; Protease Domain; Protein Isoforms; Reagent; Recommendation; Reference Standards; Reporting; Risk; Risk Factors; Role; Site; Standardization; Structure; Tandem Repeat Sequences; Technology; Testing; Therapeutic; Translating; Triglycerides; Work; World Health Organization; apolipoprotein B-100; apolipoprotein Lp(a+); cardiovascular disorder risk; cardiovascular risk factor; clinical application; clinical care; ethnic difference; follow-up; genetic risk factor; human disease; improved; novel; polyclonal antibody; racial difference; service providers; targeted treatment; validation studies; working group

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.

该提案旨在产生新颖的、广泛使用的试剂和方法来改善 测量 Lp(a) 水平以改善患者护理。 Lp(a) 水平升高非常普遍，并且 通常被认为是 CVD 的一个独立的、遗传的、可能的因果危险因素。尽管 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 由于其独特的多个相同的三环重复结构。重大技术和 方法学上的差距限制了临床实验室 Lp(a) 测量的准确性 和临床水平。主要限制是缺乏广泛可用的、全球标准化的诊断方法 方法，特别是仅与 Lp(a) 结合一次的单克隆抗体，可用于准确地 定量 Lp(a)。缺乏标准化可能会因错误分配 Lp(a) 风险而产生不良临床后遗症 治疗的阈值或目标。由于上述限制，FDA 尚未批准任何 Lp(a) 摩尔浓度测定。 NHLBI Lp(a) 工作组于 2017 年和 2019 年组织了 2 次研讨会 并建议所有利益相关者之间进行建设性合作，以确保标准化和 协调 Lp(a) 测定并使用单克隆开发独立于亚型的测定 特异性针对 apo(a) 上某一位点的抗体。为了解决高血压患者护理方面的这些差距 Lp(a)，我们提出以下具体目标：1-开发和验证独立于异构体的 Lp(a) 检测 使用最近生成的不依赖异构体的单克隆抗体； 2- 生成第二个异构体- 独立的单克隆抗体，以促进第一个独立于亚型的非 ELISA 的开发 适用于医院和商业实验室的方法。我们将与 CDC/IFCC 合作 在临床实验室界面验证这种新的 ELISA； 3-将这些新颖的检测方法应用于临床 可转化为人类疾病的数据集，包括种族/民族差异的研究、反义 Lp(a)- 降低治疗和 CVD 结果研究。