Novel Therapy for Long QT Syndrome

长 QT 综合征的新疗法

• 批准号: 9457493
• 负责人: Saumya Das
• 金额: $ 59.92万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 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/9457493
• 关键词: Adenosine; Adrenergic beta-Antagonists; Adverse effects; Affect; Agonist; Animals; Arrhythmia; Binding; Biological Assay; Biology; Cardiac; Cavia; Cell model; Cells; Cessation of life; Data; Diagnosis; Drug Kinetics; Emotional; Event; Family; Functional disorder; Genetic study; Goals; Half-Life; Hereditary Disease; Human; Implantable Defibrillators; Individual; 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; analog; base; design; drug candidate; experimental study; human stem cells; improved; in vivo; induced pluripotent stem cell; novel; novel therapeutic intervention; novel therapeutics; patch clamp; phase III trial; primary endpoint; prototype; safety and feasibility; small molecule; tool

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 先天长QT综合征（LQTS）是一种遗传性疾病，影响其他健康的个体和 由于心律不齐而导致猝死的风险增加。 LQT会影响2500个个人中的1个，并且 每年导致4,000例美国死亡。但是，在我们对 基本生物学，治疗方案仍然很差。所有LQT患者均在Beta-Blockers中治疗 努力降低精确或猝死的风险。 β受体阻滞剂不纠正基础QT间隔 延长，但有助于减少心律不齐的触发因素。 25％的LQT受试者将拥有 心脏事件目的地β受体阻滞剂，在5％的情况下，事件是突然死亡。对于那些存活的患者 建议在β受体阻滞剂上，可植入的除颤器（ICD）。这样的患者通常很年轻， 加剧了ICD疗法的不良影响，随着多次ICD电池的变化，虚假的ICD冲击和 一生中的领导修订。纠正基础生理学的疗法将被热切接受 减少心律不齐的持续风险。 以前为开发QT缩短药物的努力未成功，部分原因是缩短过多 QT间隔。这种“过度杂交”会导致短暂的QT综合征，这可能比 长QT综合征。因此，任何用于LQT的候选药物都必须具有限制QT缩短的方法 影响。 2011年，我们的实验室发现了一类新型的小分子化合物，具有有益的活性 长QT综合征的斑马鱼模型。从那时起，我们就将这个化合物类移动到 以下方式：1）在斑马鱼，豚鼠，兔模型和人类干细胞模型中建立效率 LQTS，2）进行了初步结构活动关系研究，提高了50倍的效力， 3）进行了初步实验，该实验证明了自限动作的安全性，以区分 我们从先前的治疗方法到LQT的化合物类别，4）确定了我们热门的关键目标 改善体内短循环半衰期的化合物系列，5）将2mmb确定为 腺苷敏感的钾电流IKATP。 我们的目标是将这类化合物进一步发展为长QT综合征的治疗疗法 通过以下特定目的：1）对分子机制进行机械研究 2mmb的动作，2）更详细地探索苯甲胺类别的安全性 化合物和3）对2mmb的100个新结构类似物进行结构活性研究。 我们组装了团队和工具来进行这些实验，这些实验将提供关键信息 关于新型热方法治疗长QT综合征的可行性和安全性。 最终可释放是这种威胁生命的综合症的一种新型疗法，它声称生命 健康的年轻人。