Impact of PCSK9 inhibition on abdominal aortic aneurysm pathobiology and growth

PCSK9 抑制对腹主动脉瘤病理学和生长的影响

• 批准号: 10566800
• 负责人: Scott Michael Damrauer
• 金额: $ 66.35万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-01 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10566800
• 关键词: Abdominal Aortic Aneurysm; Affect; Age Years; Aneurysm; Anti-Inflammatory Agents; Aorta; Atherosclerosis; Biological Assay; Cessation of life; Chronic; Clinical; Clinical Trials; Data; Development; Dilatation - action; Enzymes; European ancestry; Experimental Models; Familial Hypercholesterolemia; Future; Gelatinase B; Genetic; Growth; Human; Human Genetics; Hyperlipidemia; Immunofluorescence Immunologic; Individual; Inflammation; Inflammatory; Interleukin-6; Knowledge; LDL Cholesterol Lipoproteins; Life; Link; Lipids; Low Density Lipoprotein Receptor; Low-Density Lipoproteins; Macrophage; Measurement; Measures; Medical; Meta-Analysis; Operative Surgical Procedures; Organ Donor; Pharmaceutical Preparations; Pharmacogenetics; Pharmacological Treatment; Placebo Control; Placebos; Population; Positioning Attribute; Prevention; Production; Proprotein Convertases; Randomized; Randomized, Controlled Trials; Reporting; Research; Risk; Role; Rupture; Schedule; Secondary Prevention; Smooth Muscle Myocytes; Subcutaneous Injections; Subtilisins; Testing; Therapeutic; Time; Tissues; United States; Variant; Work; ancestry analysis; blind; cell type; cohort; cytokine; design; efficacious intervention; efficacy clinical trial; efficacy evaluation; efficacy trial; experimental study; genetic approach; genome wide association study; genome-wide; human subject; immune cell infiltrate; inhibitor; monocyte; operation; pharmacologic; prevent; primary outcome; repaired; secondary outcome; single nucleus RNA-sequencing; transcriptome sequencing

PROJECT SUMMARY / ABSTRACT Abdominal aortic aneurysm (AAA) is a life-threatening condition in which progressive dilatation of the infrarenal aorta leads to rupture. With ~2.3 million prevalent cases in the United States, AAA afflicts ~4% of the population ≥ 65 years of age and is responsible for ~41,000 deaths annually. No medical therapies exist that prevent AAA, AAA growth, rupture, or aneurysm-related death. The only efficacious intervention is surgery. Genome-wide association studies (GWAS) and preliminary pharmacogenetic causal inference studies from AAA GWAS demonstrate that both LDL-C lowering and PCSK9 inhibition are protective of AAA. The greatest therapeutic opportunities for pharmacological treatment of AAA lie in prevention of aneurysm expansion in individuals with small AAA. Despite our team's robust evidence linking LDL-C and PCSK9 to the development of AAA, their causal role in AAA growth remains unknown and the data to support conducting a large-scale efficacy trial is lacking. This project will leverage two orthogonal approaches to generate data that supports the role of LDL-C in AAA growth and that intensive LDL-C lowering with PCSK9 inhibitors will protect against aneurysm expansion. First, we will perform a multi-ancestry meta-analysis of GWAS of AAA growth rate and leverage these data to conduct genetic causal inference experiments interrogating the role of PCSK9 and LDL-c in AAA expansion. Second, we will conduct a quadruple-blind, randomized, placebo-controlled mechanistic clinical trial to test the effect of intensive short-term LDL-C lowering with PCSK9 inhibition on inflammation in the aneurysmal aortic wall; the primary outcome will be the production of the inflammatory cytokine interleukin 6 (IL-6) monocytes/macrophages in the aortic wall as measured by single nucleus RNA sequencing and confirmed by bulk RNA sequencing tissue- based immunofluorescence. Key secondary outcomes include: 1) matrix metalloproteinase 9 (MMP-9) production and activity; 2) relative numbers, cell type distribution, and inflammatory state of infiltrating immune cells; and 3) the relative number and proliferative/contractile state of aortic smooth muscle cells in the aortic wall. Successfully completing the proposed research will establish causal evidence linking LDL-C and AAA growth, and the ability to modulate this with PCSK9 inhibition. It will provide human mechanistic evidence that PCSK9 inhibitors induce anti-inflammatory changes in aneurysmal aortic wall that protect from aneurysm expansion. These data will provide the justification for a future large-scale randomized controlled trial to assess the efficacy of PCSK9 inhibitors to treat AAA.

项目总结/摘要 腹主动脉瘤（AAA）是一种危及生命的疾病，其中肾下动脉进行性扩张， 主动脉破裂美国约有230万流行病例，AAA影响约4%的人口 年龄≥ 65岁，每年造成约41，000例死亡。没有预防AAA的医学疗法， 腹主动脉瘤生长、破裂或腹主动脉瘤相关死亡。唯一有效的干预措施是手术。 AAA的全基因组关联研究（GWAS）和初步药物遗传学因果推断研究 GWAS证明LDL-C降低和PCSK 9抑制均对AAA具有保护作用。最伟大的 药物治疗AAA的治疗机会在于预防动脉瘤扩张， 小AAA的人。尽管我们的团队有强有力的证据将LDL-C和PCSK 9与发展联系起来， 的AAA，他们在AAA增长的因果作用仍然未知，数据支持进行大规模的 缺乏疗效试验。 本项目将利用两种正交方法生成支持LDL-C在AAA中作用的数据 PCSK9抑制剂可显著降低LDL-C水平，从而防止动脉瘤扩张。第一、 我们将对AAA增长率的GWAS进行多血统荟萃分析，并利用这些数据进行 遗传因果推理实验，询问PCSK 9和LDL-c在AAA扩张中的作用。二是 将进行一项四盲、随机、安慰剂对照的机制临床试验，以测试 短期LDL-C显著降低，同时PCSK 9抑制了主动脉壁炎症; 主要结果将是炎症细胞因子白细胞介素6（IL-6）单核细胞/巨噬细胞的产生 在主动脉壁中，通过单核RNA测序测量并通过批量RNA测序组织证实- 基于免疫荧光。关键次要结局包括：1）基质金属蛋白酶9（MMP-9） 2）浸润性免疫球蛋白的相对数量、细胞类型分布和炎症状态; 细胞;和3）主动脉壁中主动脉平滑肌细胞的相对数量和增殖/收缩状态。 成功完成拟议的研究将建立联系LDL-C和AAA增长的因果证据， 以及通过PCSK9抑制来调节这一点的能力。它将为PCSK 9提供人类机械证据， 抑制剂诱导动脉瘤主动脉壁的抗炎变化，保护动脉瘤不扩张。 这些数据将为将来进行大规模随机对照试验以评估疗效提供依据 PCSK9抑制剂来治疗AAA。