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，影响其他健康个体， 由于心律失常而导致猝死的风险增加。LQTS影响1/2500的个体， 每年导致美国4,000人死亡然而，尽管我们在理解上取得了重大进展， 基础生物学，治疗选择仍然很差。所有LQTS患者均接受β受体阻滞剂治疗， 努力减少昏厥或猝死的风险。β受体阻滞剂不能纠正基础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 尽管使用了β受体阻滞剂，但仍有5%的患者发生心脏事件，5%的患者发生猝死。对于那些活下来的病人来说 推荐使用β受体阻滞剂、植入式除颤器（ICD）。这类患者通常很年轻， 复合ICD治疗的不良反应，多次ICD电池更换，假性ICD电击和 在他们的一生中引领着修订。纠正潜在生理机能的疗法将被人们热切接受 以降低心律失常的风险。 以前开发QT缩短药物的努力一直不成功，部分原因是缩短过度 QT间期。这种“过短”会导致短QT综合征，其严重程度可能与 长QT综合征。因此，任何LQTS的候选药物都必须具有限制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， 长QT综合征的斑马鱼模型。从那时起，我们就把这个复合类向前推进， 1）在斑马鱼、豚鼠、兔模型和人干细胞模型中建立功效 2）进行初步的结构活性关系研究，将效力提高50倍， 3)进行了初步实验，证明了自限性作用的安全性， 我们的化合物类从以前的治疗方法LQTS，和4）确定了一个关键目标，我们的打击 化合物系列在改善体内短循环半衰期中的作用，和5）鉴定2 MMB作为 腺苷敏感钾电流IKATP。 我们的目标是进一步开发这类化合物，使其成为治疗长QT综合征的药物 通过以下具体目标：1）进行分子机制的机制研究， 2）为了更详细地探索苯甲酰苯胺类药物的安全性特征， 3）对100个2 MMB的新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，这些实验将提供关键信息。 关于一种新的治疗方法治疗长QT综合征的可行性和安全性。的 最终交付的是一种新的治疗方法，用于这种危及生命的综合症， 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.