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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.

项目摘要/摘要自身免疫作为心律失常的一种新的致病机制日益被人们所认识。几个已鉴定出致心律失常的自身抗体，可与不同类型的表面蛋白发生交叉反应关键涉及心肌细胞电生理学，主要是离子通道(自身免疫性心脏通道病)。具体地说，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间期综合征(LQTS)，这种疾病会增加危及生命的风险室性心律失常，特别是尖端扭矩(TDP)和心脏性猝死。最多的研究的自身免疫性LQTS与循环中抗Ro/SSA抗体的存在有关 (抗Ro抗体)，常见于自身免疫性疾病患者，但也有相当比例的显然健康的受试者在普通人群中。越来越多的证据表明，抗Ro抗体可以通过与细胞外孔区域的直接抑制交叉反应显著延迟心室复极人类乙醚-A-GO-GO相关基因K+通道(HERG-K+)，导致更高的抗Ro倾向 ABS阳性者易发生LQTS和室性心律失常/TDP。最近的人口数据表明循环抗Ro抗体携带者发生LQTS的风险显著增加，与病史无关明显的自身免疫性疾病。在这里，我们假设诱饵多肽，旨在模仿交叉- Ro/SSA抗原和HERG-K+通道S5-S6孔区均存在反应性B细胞表位，Can 中和抗Ro抗体，从而正常化或防止QT间期延长。因此，这种诱饵多肽抗Ro单抗导致的LQTS、相关的TDP和心脏性猝死的创新治疗工具。在这项目，我们的目标是开发这些工具并测试分子诱饵多肽假说，目标有3个：1) 验证交叉反应表位假设并将诱骗分子优化为有效的生物药物候选；2)通过给小鼠体内动物模型注射诱饵多肽来使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在心肌细胞水平上，多肽可使体表心电图上的QTC延长正常化。总而言之，在本申请中开发的新诱骗多肽可能阐明抗Ro抗体如何有助于心律失常给公众带来的健康负担。此外，这项研究还可以实现新的认识抗Ro抗体的病理生理机制为临床治疗开辟新的方向减轻这一负担，包括将我们的诱饵多肽疗法推进到获得许可的毒品。最后，一个新的隐藏的危险因素导致危及生命的室性心律失常和猝发一般人群中的心源性死亡事件可能会被揭示和治疗。