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.

项目摘要 /摘要 腹主动脉瘤（AAA）是一种威胁生命的疾病 主动脉导致破裂。 AAA分支机构约有230万例，约有4％的人口 ≥65岁，每年造成约41,000人死亡。没有医疗疗法可防止AAA， AAA生长，破裂或动脉瘤相关的死亡。唯一有效的干预是手术。 全基因组关联研究（GWAS）和AAA的初步药物结肠遗传因果推断研究 GWAS表明LDL-C降低和PCSK9抑制均受AAA的保护。最伟大的 AAA的药物治疗的治疗机会在于预防动脉瘤扩展 患有小型AAA的人。尽管我们的团队有力的证据将LDL-C和PCSK9与开发联系起来 在AAA中，它们在AAA增长中的因果作用仍然未知，并且数据支持进行大规模的数据 缺乏功效试验。 该项目将利用两种正交方法来生成支持LDL-C在AAA中角色的数据 生长以及通过PCSK9抑制剂降低强化的LDL-C可以预防动脉瘤扩张。第一的， 我们将对AAA增长率的GWA进行多功能荟萃分析，并利用这些数据进行 遗传因果推理实验询问了PCSK9和LDL-C在AAA扩张中的作用。第二，我们 将进行四倍盲，随机，安慰剂对照的机械临床试验，以测试 PCSK9对动脉瘤主动脉壁的注射抑制PCSK9降低了密集的短期LDL-C降低；这 主要结果将是炎性细胞因子白介素6（IL-6）单核细胞/巨噬细胞的产生 通过单核RNA测序测量的主动脉壁，并通过大量RNA测序组织确认 基于免疫荧光。关键次要结果包括：1）基质金属蛋白酶9（MMP-9） 生产和活动； 2）相对数量，细胞类型分布和浸润性免疫的炎症状态 细胞； 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有关LDL-C和AAA增长的因果证据， 以及通过PCSK9抑制进行调节的能力。它将提供PCSK9的人类机械证据 抑制剂会诱导可保护动脉瘤扩张的动脉瘤主动脉壁的抗炎变化。 这些数据将为未来的大规模随机对照试验提供理由，以评估效率 PCSK9抑制剂的治疗AAA。