Plasma Progerin in Patients With Hutchinson-Gilford Progeria Syndrome: Immunoassay Development and Clinical Evaluation.
Plasma Progerin in Patients With Hutchinson-Gilford Progeria Syndrome: Immunoassay Development and Clinical Evaluation.
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DOI：
10.1161/circulationaha.122.060002
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发表时间：
2023-06-06
期刊：
影响因子：
37.8
通讯作者：
Kleinman ME
中科院分区：
文献类型：
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作者：
Gordon LB;Norris W;Hamren S;Goodson R;LeClair J;Massaro J;Lyass A;D'Agostino RB Sr;Tuminelli K;Kieran MW;Kleinman ME
Hutchinson-Gilford早衰综合征（HGPS）是一种由一种名为早老蛋白的有毒蛋白引起的超罕见、致命、过早衰老的疾病。循环早老蛋白以前没有被检测到，排除了使用现成的生物样品进行研究。本研究旨在开发血浆早老蛋白测定法，以评估早老蛋白的量、对早老蛋白靶向治疗的反应以及与患者生存的关系。由The Progeria Research Foundation Cell and Tissue Bank从非HGPS队列的横截面和HGPS队列的纵向收集生物样品。在波士顿儿童医院进行的3项连续开放标签临床试验中，HGPS捐赠发生在基线和间歇性，同时接受法尼基化抑制剂洛那法尼±普伐他汀和唑来膦酸盐治疗，治疗时间总计>10年。开发了一种具有预定性能参数的超灵敏单分子计数早老蛋白免疫测定法。患者组内和患者组间的统计是描述性的。早老蛋白和生存之间的关系进行了评估，通过使用联合建模与时间依赖性斜率参数化。该方法的动态检测范围为59 ~ 30000 pg/mL（R2=0.9987）。无核纤层蛋白A交叉反应。非HGPS受试者的平均血浆早老素（n=69; 39名男性，30名女性;年龄，0.2-71.3岁）为351±251 pg/mL，在未接受过药物治疗的HGPS参与者中，（n=74; 37名女性，37名男性;年龄，2.1-17.5岁）为33 261±12 346 pg/mL，反映受影响儿童增加了95倍（P<0.0001）。不同性别的早老蛋白水平无差异（P=0.99）。洛那法尼治疗导致每次访视的平均早老蛋白较基线降低35%至62%（所有P<0.005）;加用普伐他汀和唑来膦酸盐并未增强效果。早老素水平在治疗后4个月内下降，并保持较低水平长达10年。早老蛋白降低的幅度与患者存活率呈正相关（P<0.0001;即，15000 pg/mL降低导致死亡风险降低63.9%）。对于任何给定的早老蛋白降低，预期寿命随着治疗持续时间的延长而递增。开发了用于早老蛋白的灵敏的定量免疫测定，并用于证明HGPS血浆中的高早老蛋白水平，其随着洛那法尼治疗而降低。存活率的改善程度与早老蛋白降低的幅度和较低水平的持续时间相关。因此，血浆早老蛋白是HGPS的生物标志物，其减少使得能够对早老蛋白靶向治疗功效进行短期和长期评估。URL：https://www.clinicaltrials.gov。唯一标识符：NCT 00879034和NCT 00916747。
Hutchinson-Gilford progeria syndrome (HGPS) is an ultrarare, fatal, premature aging disease caused by a toxic protein called progerin. Circulating progerin has not been previously detected, precluding research using readily available biological samples. This study aimed to develop a plasma progerin assay to evaluate progerin’s quantity, response to progerin-targeted therapy, and relationship to patient survival. Biological samples were collected by The Progeria Research Foundation Cell and Tissue Bank from a non-HGPS cohort cross-sectionally and a HGPS cohort longitudinally. HGPS donations occurred at baseline and intermittently while treated with farnesylation inhibitors lonafarnib±pravastatin and zoledronate, within 3 sequential open-label clinical trials at Boston Children’s Hospital totaling >10 years of treatment. An ultrasensitive single-molecule counting progerin immunoassay was developed with prespecified performance parameters. Intra- and interpatient group statistics were descriptive. The relationship between progerin and survival was assessed by using joint modeling with time-dependent slopes parameterization. The assay’s dynamic detection range was 59 to 30 000 pg/mL (R2=0.9987). There was no lamin A cross-reactivity. Mean plasma progerin in non-HGPS participants (n=69; 39 male, 30 female; age, 0.2–71.3 years) was 351±251 pg/mL, and in drug-naive participants with HGPS (n=74; 37 female, 37 male; age, 2.1–17.5 years) was 33 261±12 346 pg/mL, reflecting a 95-fold increase in affected children (P<0.0001). Progerin levels did not differ by sex (P=0.99). Lonafarnib treatment resulted in an average per-visit progerin decrease from baseline of between 35% to 62% (all P<0.005); effects were not augmented by adding pravastatin and zoledronate. Progerin levels fell within 4 months of therapy and remained lower for up to 10 years. The magnitude of progerin decrease positively associated with patient survival (P<0.0001; ie, 15 000 pg/mL decrease yields a 63.9% decreased risk of death). For any given decrease in progerin, life expectancy incrementally increased with longer treatment duration. A sensitive, quantitative immunoassay for progerin was developed and used to demonstrate high progerin levels in HGPS plasma that decreased with lonafarnib therapy. The extent of improved survival was associated with both the magnitude of progerin decrease and duration at lower levels. Thus, plasma progerin is a biomarker for HGPS whose reduction enables short- and long-term assessment of progerin-targeted treatment efficacy. URL: https://www.clinicaltrials.gov. Unique identifiers: NCT00879034 and NCT00916747.
影响因子：
5.6
作者：
通讯作者：
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