Novel Therapy for Long QT Syndrome

摘要 先天性长QT综合征(LQTS)是一种遗传性疾病，影响其他健康的人和 会增加因心律失常而猝死的风险。LQTS影响2500人中的1人， 导致美国每年4000人死亡。然而，尽管我们对 在基础生物学方面，治疗选择仍然很差。所有LQTS患者都接受β-受体阻滞剂的治疗 降低晕倒或猝死风险的努力。β-受体阻滞剂不能纠正潜在的QT间期 延长，但有助于减少心律失常的触发因素。25%的LQTS受试者将拥有 尽管服用了β-受体阻滞剂，但仍有心脏事件发生，5%的事件是猝死。对于那些幸存下来的患者 推荐使用β-受体阻滞剂、植入式除颤器(ICD)。这样的病人通常都很年轻， ICD治疗的不良反应，包括多次更换ICD电池，虚假的ICD电击和 在他们的一生中引领着修改。纠正潜在生理学的疗法将被热切地接受 以降低持续发生心律失常的风险。 以前开发QT缩短药物的努力都没有成功，部分原因是过度缩短 QT间期。这种“过度缩短”会导致短QT综合征，其严重程度可能与 QT间期延长综合征。因此，任何治疗LQTS的候选药物都必须有限制QT缩短的方法 效果。2011年，我们的实验室发现了一类新的小分子化合物，在 长QT间期综合征斑马鱼模型。从那时起，我们将这个复合类向前移动到 以下方法：1)在斑马鱼、豚鼠、兔模型和人类干细胞模型中建立疗效 2)进行了初步的构效关系研究，使效价提高了50倍， 3)进行了初步实验，证明了自我限制行动的安全性 我们以前的LQTS治疗方法的复合类，以及4)为我们的HIT确定了一个关键目标 化合物系列在改善体内较短的循环半衰期方面，以及5)确定2MMB是一种 腺苷敏感钾电流IKATP。 我们的目标是将这类化合物进一步开发为治疗长QT综合征的药物 通过以下具体目标：1)从分子机制上研究黄曲霉毒素 2MMB的行动，2)更详细地探索苯苯胺类药物的安全性 化合物，3)进行100个新的2MMB结构类似物的结构活性研究。 我们已经组建了团队和工具来进行这些实验，这些实验将提供关键信息 关于一种新的治疗长QT综合征的方法的可行性和安全性。这个 最终交付是一种治疗这种危及生命的综合征的新疗法，这种综合症夺走了其他人的生命 健康的年轻人。

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.