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; 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.

该提案旨在生成新颖的，广泛可用的试剂和方法，以改善 LP（a）水平的测量以改善患者护理。 LP（a）级别高度普遍，并且 普遍认为是CVD的独立，遗传和可能的因果风险因素。虽然LP（a）水平 是在临床实验室中测量的，它是准确测量的最困难的实验室分析物之一 由于其具有多个相同的kringle重复序列的独特结构。重要的技术和 存在限制LP（a）测量在临床实验室的准确性的方法论差距 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，特别是仅与LP结合一次的单克隆抗体（A） 定量LP（a）。缺乏标准化可能会通过错误分配LP（a）风险而具有不良临床序列。 阈值或治疗目标。由于上述局限性，FDA尚未批准任何LP（a） 分析摩尔浓度。 NHLBI LP（A）的NHLBI工作组在2017年和2019年组织了2个研讨会 并建议所有利益相关者之间的建设性协作，以确保标准化和 LP（a）测定的协调并开发使用单克隆独立的同工型的测定 特定于Apo（a）上一个位点的抗体。解决这些差距在患者升高的患者护理中 LP（a），我们提出以下特定目的：1-开发和验证同工型独立LP（a）测定法 带有最近产生的同工型单克隆抗体； 2-生成第二个同工型 - 独立的单克隆抗体，以促进第一，非同工型非依赖性的非Elisa的发展 方法可以适应医院和商业实验室。我们将与CDC/IFCC合作 在临床实验室界面上验证这种新ELISA； 3-将这些新颖的测定法应用于临床 用于转化为人类疾病的数据集，包括对种族/种族差异的研究，反义有限责任（a） - 降低治疗和CVD结果研究。