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Rescue of Autoimmune-Associated Long QT Syndrome by Decoy Peptides

诱饵肽拯救自身免疫相关的长 QT 综合征

基本信息

批准号：
10687180
负责人：
Mohamed Boutjdir
金额：
$ 59.22万
依托单位：
NARROWS INSTITUTE FOR BIOMEDICAL RES INC
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-19 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10687180
关键词：
Acceleration Action Potentials Affinity Amino Acid Sequence Animal Model Antibodies Antigens Arrhythmia Attention Autoantibodies Autoimmune Autoimmune Diseases Autoimmunity B-Lymphocyte Epitopes Binding Sites Biological Cardiac Cardiac Myocytes Cavia Classification Clinical Cross Reactions Data Developed Countries Development Diagnosis Disease Electrocardiogram Electrophysiology (science)Enhancers Enzyme-Linked Immunosorbent Assay Epitopes Ethers Event Future General Population Genes Genetic Heart Abnormalities High Prevalence Human Immunization Immunize Immunoglobulin G Incidence Individual Ion Channel Ions Licensing Life Long QT Syndrome Mediating Membrane Proteins Molecular Monitor Monoclonal Antibodies Morbidity - disease rate Nuclear Pathogenesis Pathogenicity Patients Peptides Pharmaceutical Preparations Population Positioning Attribute Potassium Channel Public Health Recording of previous events Research Risk Risk Factors SS-A antibodies SS-A antigen Surface Technology Testing Therapeutic Torsades de Pointes Translating Translations Ventricular Ventricular Arrhythmia Work cross reactivity design drug candidate extracellular heart rhythm in vivo inhibiting antibody innovation molecular modeling mortality mutation screening novel novel strategies novel therapeutics peptide drug peptidomimetics pre-clinical prevent rational design research clinical testing sudden cardiac death three dimensional structure three-dimensional visualization time interval tool

项目摘要

PROJECT SUMMARY/ABSTRACT Autoimmunity is increasingly recognized as a novel pathogenic mechanism for cardiac arrhythmias. Several arrhythmogenic autoantibodies have been identified, cross-reacting with different types of surface proteins critically involved in cardiomyocyte electrophysiology, primarily ion channels (autoimmune cardiac channelopathies). Specifically, some of these autoantibodies can prolong the action potential duration, leading to acquired long-QT syndrome (LQTS), a condition known to increase the risk of life-threatening ventricular arrhythmias, particularly Torsades de Pointes (TdP) and sudden cardiac death. The most investigated form of autoimmune LQTS is associated with the presence of circulating anti-Ro/SSA antibodies (anti-Ro Abs), frequently found in patients with autoimmune diseases, but also in a significant proportion of apparently healthy subjects in the general population. Accumulating evidence indicates that anti-Ro Abs can markedly delay ventricular repolarization via a direct inhibitory cross-reaction with the extracellular pore region of the human ether-à-go-go related gene K+ channel (hERG-K+), resulting in a higher propensity for anti-Ro Abs-positive subjects to develop LQTS and ventricular arrhythmias/TdP. Recent population data demonstrate that the risk of LQTS in subjects with circulating anti-Ro Abs is significantly increased, independent of a history of overt autoimmune diseases. Here, we hypothesize that decoy peptides, designed to mimic the cross- reactive B-cell epitope present on both Ro/SSA antigen and hERG-K+ channel S5-S6 pore region, can neutralize anti-Ro Abs and thus normalize or prevent QTc prolongation. Such decoy peptides are therefore innovative therapeutic tools for anti-Ro Abs induced LQTS, associated TdP and sudden cardiac death. In this project, we aim to develop these tools and test the molecular, decoy peptides hypothesis with 3 aims: 1) Validate the cross-reactive epitope hypothesis and optimize the decoy molecule into a valid biologic drug candidate; 2) Normalize QTc prolongation by the administration of decoy peptides to an in vivo animal model of autoimmune associated LQTS and 3) investigate the electrophysiological mechanisms by which the decoy peptides normalize QTc prolongation on the surface ECG at the cardiomyicyte level. Collectively, the new decoy peptides developed in this application may illuminate how anti-Ro Abs contribute to the public health burden imposed by cardiac arrhythmias. In addition, this research could achieve new understanding of pathophysiologic mechanisms of anti-Ro Abs and open a new therapeutic direction for mitigating this burden, including the possibility of advancing our decoy peptide therapy towards a licensed drug. Finally, a new concealed risk factor contributing to life-threatening ventricular arrhythmias and sudden cardiac death events in the general population may be revealed and treated.

项目概要/摘要自身免疫越来越被认为是心律失常的一种新的致病机制。一些致心律失常自身抗体已被鉴定，与不同类型的表面蛋白发生交叉反应关键参与心肌细胞电生理学，主要是离子通道（自身免疫心脏通道病）。具体来说，其中一些自身抗体可以延长动作电位持续时间，导致获得性长 QT 综合征 (LQTS)，这种情况已知会增加危及生命的风险室性心律失常，特别是尖端扭转型室速 (TdP) 和心源性猝死。最研究的自身免疫性 LQTS 形式与循环抗 Ro/SSA 抗体的存在相关（抗 Ro Abs），常见于自身免疫性疾病患者，但也存在很大比例一般人群中明显健康的受试者。越来越多的证据表明抗 Ro Abs 可以通过与细胞外孔区域的直接抑制性交叉反应，显着延迟心室复极人类 ether-à-go-go 相关基因 K+ 通道 (hERG-K+)，导致抗 Ro 的倾向更高 Abs 阳性受试者会出现 LQTS 和室性心律失常/TdP。最近的人口数据表明循环抗 Ro 抗体受试者的 LQTS 风险显着增加，与病史无关明显的自身免疫性疾病。在这里，我们假设诱饵肽旨在模仿交叉 Ro/SSA 抗原和 hERG-K+ 通道 S5-S6 孔区域上都存在反应性 B 细胞表位，可以中和抗 Ro Ab，从而使 QTc 正常化或防止 QTc 延长。因此，此类诱饵肽是针对抗 Ro Abs 诱导的 LQTS、相关 TdP 和心源性猝死的创新治疗工具。在这个项目中，我们的目标是开发这些工具并测试分子诱饵肽假说，其目标有 3 个：1) 验证交叉反应表位假设并将诱饵分子优化为有效的生物药物候选人; 2) 通过向体内动物模型施用诱饵肽来使 QTc 延长正常化自身免疫相关的 LQTS 和 3) 研究诱饵的电生理机制肽使心肌细胞水平的表面心电图上的 QTc 延长正常化。总的来说，本申请中开发的新诱饵肽可能会阐明抗 Ro Abs 如何促进心律失常造成的公共卫生负担。此外，这项研究还可以取得新的成果理解抗Ro抗体的病理生理机制并开辟新的治疗方向减轻这种负担，包括将我们的诱饵肽疗法推向许可的可能性药品。最后，一个新的隐藏危险因素会导致危及生命的室性心律失常和突发性心律失常。一般人群中的心脏死亡事件可能会被发现并得到治疗。