Translating Lp(a) biology to clinical applications

将 Lp(a) 生物学转化为临床应用

• 批准号: 10446215
• 负责人: SOTIRIOS TSIMIKAS
• 金额: $ 64.9万
• 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/10446215
• 关键词: Address; Aortic Valve Stenosis; Apolipoproteins A; Awareness; Binding; Biological; Biological Assay; Biology; Carbohydrates; Cardiovascular Diseases; Centers for Disease Control and Prevention (U.S.); Cholesterol; Cholesterol Esters; Clinical; Clinical Chemistry; 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 Name; 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; Reference Standards; Reporting; Risk; Risk Factors; Role; Site; Standardization; Structure; Tandem Repeat Sequences; Testing; Therapeutic; Time; Translating; Triglycerides; Work; World Health Organization; apolipoprotein B-100; apolipoprotein Lp(a+); base; calcification; cardiovascular disorder risk; cardiovascular risk factor; clinical application; clinical care; ethnic difference; follow-up; genetic risk factor; human disease; improved; novel; polyclonal antibody; racial and ethnic; 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.

这项提议旨在产生新的、广泛可用的试剂和方法，以改善 测量Lp(A)水平，以改善患者护理。Lp(A)水平升高非常普遍， 被普遍认为是心血管疾病的一个独立的、遗传的和可能的因果风险因素。虽然Lp(A)水平 在临床实验室中被测量，它是最难准确测量的实验室分析之一。 由于其独特的结构，多个相同的kringle重复。重要的技术和 方法学上的差距限制了两个临床实验室Lp(A)测量的准确性 和临床水平。主要的限制是缺乏广泛可用的、全球标准化的诊断 方法，特别是仅与Lp(A)结合一次的单抗，可用于准确地 Lp(A)定量。这种缺乏标准化可能会因错误分配Lp(A)风险而产生不利的临床后遗症 治疗的阈值或目标。由于上述限制，FDA尚未批准任何LP(A) 摩尔浓度测定法。NHLBI关于LP(A)的工作组在2017年和2019年举办了2次讲习班 并建议所有利益攸关方开展建设性合作，以确保标准化和 协调Lp(A)分析并开发使用单克隆的不依赖于异构体的分析 针对载脂蛋白(A)上某一部位的抗体。为了解决这些差距，在护理高龄患者 Lp(A)的基础上，我们提出了以下具体目标：1.建立和验证一种不依赖于异构体的Lp(A)分析方法 与最近产生的不依赖于异构体的单抗；2-产生第二个异构体- 独立的单抗有助于开发第一种不依赖异构体的非酶联免疫吸附试验 适用于医院和商业实验室的方法。我们将与CDC/IFCC合作， 在临床实验室界面上验证这种新的酶联免疫吸附试验；以及3-将这些新的检测方法应用于临床 人类疾病的可译性数据集，包括种族/民族差异研究，反义LP(A)- 降低治疗和心血管疾病结局研究。