Treatment With Evinacumab Links a New Pathogenic Variant in the LPL Gene to Persistent Chylomicronemia.

IF 3 Q2 ENDOCRINOLOGY & METABOLISM
Journal of the Endocrine Society Pub Date : 2025-02-14 eCollection Date: 2025-03-03 DOI:10.1210/jendso/bvaf025
Miriam Larouche, Poulabi Banerjee, Diane Brisson, Robert Pordy, Daniel Gaudet
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引用次数: 0

Abstract

Background: Persistent chylomicronemia is caused by lipoprotein lipase deficiency (LPLD) or lack of lipoprotein lipase (LPL) bioavailability. This disorder is characterized by plasma triglyceride (TG) levels above 10 mmol/L, increased acute pancreatitis risk, and features of familial chylomicronemia syndrome (FCS). Evinacumab is an angiopoietin-like protein 3 (ANGPTL3) monoclonal antibody, and its efficacy in decreasing plasma TG levels depends on LPL bioavailability.

Objective: To identify FCS-causing pathogenic variants in patients with persistent chylomicronemia treated with evinacumab.

Methods: A phase II clinical trial was conducted with evinacumab in patients with severe hypertriglyceridemia. Plasma TG values were measured at baseline and every 2 weeks for 24 weeks. Three FCS patients homozygotes for a P234L pathogenic variant in the LPL gene (HoLPL P234L) known to be associated with low postheparin LPL activity (proven LPLD) participated in the study and were used as tracers. The genotype-specific efficacy of evinacumab to decrease TG levels in other participants was compared to that achieved in HoLPL P234L patients.

Results: After 24 weeks of evinacumab treatment, TG levels decreased <20% in HoLPL P234L patients known to lack LPL. Similarly, a participant homozygote for a E282X variant in the exon 6 of the LPL gene that was suspected to be pathogenic due to its location did not respond to evinacumab (TG decreased <10% and remained >10 mmol/L).

Conclusion: The efficacy of ANGPTL3 inhibitors in decreasing TG levels is LPL-dependent. Poor response to evinacumab supports the evidence that the E282X variant in the LPL gene is pathogenic and associated with persistent chylomicronemia (FCS phenotype).

Evinacumab治疗将LPL基因中一种新的致病变异与持续性乳糜微粒血症联系起来。
背景:持续性乳糜微粒血症是由脂蛋白脂肪酶缺乏(LPLD)或缺乏脂蛋白脂肪酶(LPL)生物利用度引起的。这种疾病的特征是血浆甘油三酯(TG)水平高于10 mmol/L,急性胰腺炎风险增加,以及家族性乳糜小铁血症综合征(FCS)的特征。Evinacumab是一种血管生成素样蛋白3 (ANGPTL3)单克隆抗体,其降低血浆TG水平的功效取决于LPL的生物利用度。目的:鉴定evinacumab治疗的持续性乳糜微粒血症患者中引起fcs的致病变异。方法:对evinacumab治疗严重高甘油三酯血症患者进行II期临床试验。在基线和每2周测量一次血浆TG值,持续24周。已知与低肝素后LPL活性(已证实的LPLD)相关的LPL基因P234L致病变异(HoLPL P234L)的三名FCS患者参与了这项研究,并被用作示踪剂。evinacumab降低其他参与者TG水平的基因型特异性疗效与HoLPL P234L患者的效果进行了比较。结果:evinacumab治疗24周后,TG水平下降10 mmol/L)。结论:ANGPTL3抑制剂降低TG水平的作用依赖于lpl。对evinacumab的不良反应支持了LPL基因中的E282X变异具有致病性并与持续性乳糜微血症(FCS表型)相关的证据。
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 the Endocrine Society
Journal of the Endocrine Society Medicine-Endocrinology, Diabetes and Metabolism
CiteScore
5.50
自引率
0.00%
发文量
2039
审稿时长
9 weeks
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