Novel Therapy for Long QT Syndrome

长 QT 综合征的新疗法

基本信息

批准号：
9152955
负责人：
David J Milan
金额：
$ 60.2万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-06-01 至 2020-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9152955
关键词：
Accounting Adenosine Adrenergic beta-Antagonists Adverse effects Affect Agonist Animals Arrhythmia Binding Biological Assay Biology Cardiac Cavia Cell model Cells Cessation of life Data Diagnosis Disease Drug Kinetics Emotional Event Functional disorder Genetic study Goals Half-Life Human Implantable Defibrillators Individual Inherited Laboratories Lead Life Long QT Syndrome Medical Modeling Molecular Mechanisms of Action Nature Organ Orphan Oryctolagus cuniculus Parents Patients Permeability Pharmaceutical Preparations Photoaffinity Labels Physicians Physiology Population Potassium Rattus Risk Safety Series Shock Short QT syndrome Site-Directed Mutagenesis Sodium Structure Structure-Activity Relationship Sudden Death Surrogate Endpoint Syncope Syndrome Testing Therapeutic Time Zebrafish abstracting analog base design drug candidate human stem cells improved in vivo induced pluripotent stem cell novel novel therapeutic intervention novel therapeutics patch clamp phase III trial prototype research study small molecule tool

项目摘要

Abstract Congenital long QT syndrome (LQTS) is an inherited disease that affects otherwise healthy individuals and carries an increased risk of sudden death due to cardiac arrhythmia. LQTS affects 1 in 2500 individuals and results in 4,000 U.S. deaths annually. However, despite significant advances in our understanding of the fundamental biology, treatment options remain poor. All patients with LQTS are treated with beta-blockers in an effort to reduce the risk of fainting or sudden death. Beta-blockers do not correct the underlying QT interval prolongation, but help reduce the triggers of arrhythmias. Twenty-five percent of LQTS subjects will have cardiac events despite beta-blockers and in 5% that event is sudden death. For those patients who survive events on beta-blockers, implantable defibrillators (ICDs) are recommended. Such patients are often young, compounding the adverse effects of ICD therapy, with multiple ICD battery changes, spurious ICD shocks and lead revisions over their lifetimes. Therapies that correct the underlying physiology would be eagerly accepted to reduce ongoing risk of arrhythmias. Previous efforts to develop QT shortening drugs have been unsuccessful, in part due to excessive shortening of the QT interval. Such “overshortening” causes short QT syndrome which can be as bad as or worse than long QT syndrome. Therefore any candidate drug for LQTS must have a means of limiting the QT shortening effect. In 2011, our laboratory discovered a novel class of small molecule compounds with beneficial activity in a zebrafish model of long QT syndrome. Since that time we have moved this compound class forward in the following ways: 1) Established efficacy in zebrafish, guinea pig, rabbit models, and in human stem cell models of LQTS, 2) Conducted a preliminary structure activity relationship study, improving potency 50-fold, 3) Conducted preliminary experiments that demonstrate a safety profile of self-limited action that distinguishes our compound class from prior therapeutic approaches to LQTS, and 4) Identified a key objective for our hit compound series in improving in vivo short circulating half-life, and 5) Identified 2MMB as an activator of the adenosine sensitive potassium current IKATP. It is our goal to further develop this class of compounds into a therapeutic treatment for long QT syndrome through the following specific aims: 1) To perform mechanistic studies of the molecular mechanism of action of 2MMB, 2) To explore in greater detail the safety profile for the benzanilide class of compounds, and 3) To perform structure activity studies of 100 new structural analogs of 2MMB. We have assembled the team and the tools to conduct these experiments which will provide critical information regarding the feasibility and safety of a novel therapeutic approach to the treatment of long QT syndrome. The ultimate deliverable is a novel therapy for this life-threatening syndrome that claims the lives of otherwise healthy young individuals.

抽象的先天性长 QT 综合征 (LQTS) 是一种遗传性疾病，影响健康个体和由于心律失常导致猝死的风险增加，每 2500 人中就有 1 人受到影响。然而，尽管我们对这一问题的了解有了重大进展，但每年仍导致 4,000 人死亡。基础生物学方面，所有 LQTS 患者均接受 β 受体阻滞剂治疗。降低晕厥或猝死风险的努力并不能纠正潜在的 QT 间期。延长，但有助于减少心律失常的触发因素 25% 的 LQTS 受试者会出现这种情况。尽管使用了β受体阻滞剂，但仍会发生心脏事件，对于那些幸存的患者，5%的事件是猝死。建议使用 β 受体阻滞剂、植入式除颤器 (ICD) 此类患者通常很年轻。多次更换 ICD 电池、虚假 ICD 电击和 ICD 治疗的不良影响变得更加复杂纠正潜在生理机能的疗法将被热切接受。以减少持续发生心律失常的风险。此前开发缩短QT间期药物的努力均未成功，部分原因是缩短QT间期过度这种 QT 间期的“过度缩短”会导致短 QT 综合征，其严重程度可能与 QT 间期一样严重，甚至更严重。因此，任何治疗 LQTS 的候选药物都必须有限制 QT 缩短的方法。 2011 年，我们的实验室发现了一类具有有益活性的新型小分子化合物。长 QT 综合征的斑马鱼模型从那时起，我们就将这一复合类别向前推进。以下方式： 1) 在斑马鱼、豚鼠、兔子模型和人类干细胞模型中确定功效 LQTS，2）进行了初步的结构活性关系研究，将效力提高了50倍， 3) 进行了初步实验，证明了自我限制作用的安全性，从而区分了我们的化合物类别来自先前的 LQTS 治疗方法，并且 4) 确定了我们的成功的关键目标改善体内短循环半衰期的化合物系列，以及 5) 鉴定 2MMB 作为腺苷钾敏感电流IKATP。我们的目标是进一步开发此类化合物，用于治疗长 QT 综合征通过以下具体目标：1）对分子机制进行机理研究 2MMB 的作用，2) 更详细地探讨苯甲酰苯胺类的安全性化合物，以及 3) 对 100 个新的 2MMB 结构类似物进行结构活性研究。我们已经组建了团队和工具来进行这些实验，这将提供关键信息关于治疗长 QT 综合征的新型治疗方法的可行性和安全性。最终成果是针对这种危及生命的综合症的一种新疗法，该综合症夺走了其他人的生命健康的年轻人。