Measuring Lp(a) particles with a novel isoform-insensitive immunoassay illustrates efficacy of muvalaplin.

IF 5 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Journal of Lipid Research Pub Date : 2025-01-01 Epub Date: 2024-12-06 DOI:10.1016/j.jlr.2024.100723
Craig A Swearingen, John H Sloan, Grace M Rhodes, Robert W Siegel, Nico Bivi, Yuewei Qian, Robert J Konrad, Michael Boffa, Marlys Koschinsky, John Krege, Giacomo Ruotolo, Stephen J Nicholls, Laura F Michael, Yi Wen
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引用次数: 0

Abstract

Lipoprotein(a) [Lp(a)] is a cardiovascular risk factor, and there is considerable interest in developing Lp(a)-lowering therapeutics for cardiovascular prevention. Current commercial Lp(a) assays measure total apolipoprotein(a) [apo(a)] and may be insufficient to accurately measure Lp(a) concentrations and determine Lp(a) lowering by a new class of small-molecule Lp(a) formation inhibitors such as muvalaplin. We developed a novel immunoassay that measures only Lp(a) particles. This intact Lp(a) assay demonstrated robust analytical performance, was insensitive to apo(a) isoform size, and correlated with a liquid chromatography-tandem mass spectrometry method. Muvalaplin phase I multiple ascending dose study samples and lepodisiran, a small-interfering RNA that lowers Lp(a), phase I single ascending dose study samples were analyzed using the intact Lp(a) assay and commercial assays. The Lp(a)-lowering efficacy of muvalaplin was underestimated by the commercial assay measuring total apo(a) compared with the intact Lp(a) assay specifically measuring Lp(a) particles. In contrast, the Lp(a)-lowering effect of lepodisiran was clinically comparable between the intact Lp(a) assay and commercial assay. This novel intact Lp(a) assay provides a more accurate approach for the assessment of Lp(a)-lowering agents and the study of Lp(a)-associated risk compared with currently available assays.

用一种新型的异型不敏感免疫分析法测量Lp(a)颗粒,说明muvalaplin的有效性。
脂蛋白(a) [Lp(a)]是一种心血管危险因素,开发降低Lp(a)的治疗方法以预防心血管疾病引起了相当大的兴趣。目前的商业Lp(a)测定方法测量总载脂蛋白(a) [apo(a)],可能不足以准确测量Lp(a)浓度,并确定新一类小分子Lp(a)形成抑制剂(如muvalaplin)对Lp(a)的降低。我们开发了一种新的免疫分析法,仅测量Lp(a)颗粒。这种完整的Lp(a)分析方法具有强大的分析性能,对载脂蛋白(a)异构体大小不敏感,并与液相色谱-串联质谱法相关。Muvalaplin一期多次递增剂量研究样本和lepodisiran(一种降低Lp(a)的小干扰RNA)一期单次递增剂量研究样本使用完整Lp(a)测定法和商业测定法进行分析。与专门测量Lp(a)颗粒的完整Lp(a)试验相比,测量总载脂蛋白(a)的商业试验低估了muvalaplin降低Lp(a)的功效。相比之下,lepodisiran的Lp(a)降低效果在完整的Lp(a)试验和商业试验之间具有临床可比性。与现有的检测方法相比,这种新颖的完整Lp(a)检测方法为评估Lp(a)降低剂和研究Lp(a)相关风险提供了更准确的方法。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Journal of Lipid Research
Journal of Lipid Research 生物-生化与分子生物学
CiteScore
11.10
自引率
4.60%
发文量
146
审稿时长
41 days
期刊介绍: The Journal of Lipid Research (JLR) publishes original articles and reviews in the broadly defined area of biological lipids. We encourage the submission of manuscripts relating to lipids, including those addressing problems in biochemistry, molecular biology, structural biology, cell biology, genetics, molecular medicine, clinical medicine and metabolism. Major criteria for acceptance of articles are new insights into mechanisms of lipid function and metabolism and/or genes regulating lipid metabolism along with sound primary experimental data. Interpretation of the data is the authors’ responsibility, and speculation should be labeled as such. Manuscripts that provide new ways of purifying, identifying and quantifying lipids are invited for the Methods section of the Journal. JLR encourages contributions from investigators in all countries, but articles must be submitted in clear and concise English.
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