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.

项目摘要/摘要自身免疫性越来越被认为是心律不齐的新型致病机制。一些心律失常自身抗体已被鉴定出来，与不同类型的表面蛋白进行交叉反应主要参与心肌细胞电生理学，原发离子通道（自身免疫性心脏渠道疾病）。特别是，其中一些自身抗体可以延长动作势持续时间，导致获得的长QT综合征（LQT），这种疾病已知，旨在增加威胁生命的风险心室心律不齐，尤其是Torsades de Pointes（TDP）和猝死。最多自身免疫性LQT的研究形式与循环抗RO/SSA抗体的存在有关（抗RO ABS），经常在自身免疫性疾病的患者中发现，但也很大比例显然是一般人群中健康的受试者。积累的证据表明抗抗ABS可以通过直接抑制性交叉反应与细胞外孔区域明显延迟心室重极化人类Ether-à-go-go相关基因K+通道（HERG-K+），导致抗Ro的前景更高 ABS阳性受试者发展LQT和心室心律不齐/TDP。最近的人口数据证明在循环抗RO ABS的受试者中LQT的风险显着增加，与历史无关明显的自身免疫性疾病。在这里，我们假设诱饵刺激了，旨在模仿交叉 RO/SSA抗原和HERG-K+通道S5-S6孔区域上存在反应性B细胞发作，可以中和抗RA ABS，从而标准化或预防QTC延长。因此，这样的诱饵宠物是用于抗RO ABS诱导的LQT，相关的TDP和猝死的创新治疗工具。在这个项目，我们旨在开发这些工具并以3个目的测试分子，诱饵肽假说：1）验证交叉反应表位假说并将诱饵分子优化为有效的生物药物候选人; 2）通过将诱饵肽施用到体内动物模型，使QTC的延长归一化自身免疫性相关的LQT和3）研究诱饵的电生理机制肽在心脏杨氏水平的表面心电图上QTC延长归一化。总的来说，在本申请中开发的新诱饵petides可能会阐明抗抗ABS的贡献心律不齐施加的公共卫生伯恩。此外，这项研究可以实现新的了解抗RO ABS的病理生理机制，并为减轻这种燃烧，包括将我们的诱饵肽疗法推向许可的可能性药品。最后，一种新的隐藏危险因素，导致威胁生命的心室心律不齐和突然普通人群中的心脏死亡事件可能会被揭示和治疗。