RSK3 Anchoring Disruptor Therapy for Heart Failure

 描述(申请人提供)：病理性心脏重塑，包括心肌细胞肥大、细胞凋亡和心肌间质纤维化，构成疾病中心力衰竭的常见途径。尽管目前的药物治疗和其他减缓重塑的进展，心力衰竭的死亡率仍然很高。越来越多的患者迫切需要新的、更有效的治疗方案，以改善心力衰竭患者或易患心力衰竭患者的生存和生活质量。我们最近发现，蛋白激酶P90核糖体S6激酶3(RSK3)在病理性心脏重构的调节中起着关键作用。2013年，由Michael Kapiloff博士创立了Anchored RSK3 Inhibitors LLC，旨在开发基于RSK3抑制的新疗法，以预防和/或治疗心力衰竭。尽管RSK3在心肌细胞中的含量低于RSK蛋白激酶家族的其他成员，但RSK3仍是病理重塑所必需的。我们发现，在心肌细胞中，RSK3‘S独特的N-末端结构域与支架蛋白肌肉A-激酶锚定蛋白(mAKAP？)具有高亲和力、可调控的结合。这种新的蛋白质-蛋白质相互作用解释了该激酶亚型与支架的选择性结合。新的初步数据显示，在体外和体内表达一种锚定干扰素，阻断mAKAP？-RSK3结合，将减轻病理重塑，防止因压力超负荷而发生心力衰竭。这一STTR应用的目的是支持新腺相关病毒(AAV)基因治疗载体的开发，该载体表达RSK3锚定干扰肽。这项拟议的研究将为基于RSK3在心肌细胞内的移位来治疗和/或预防心力衰竭的新的治疗方法提供概念验证。具体目标1：锚定阻断疗法治疗压力超负荷所致心力衰竭。心肌细胞选择性表达mAKAP？RSK3结合肽(RBD)可预防体内横动脉缩窄所致的心力衰竭。在这个目标中，我们将测试RSK3锚定干扰物治疗是否可以诱导压力超负荷所致的已有病理的小鼠的反向重塑和治疗心力衰竭。具体目标2：通过锚定阻断疗法预防心肌梗死所致心力衰竭。为此，我们将测试AAV-RBD是否可以阻止心肌梗死后的重塑，而不会对心肌梗死面积或疤痕形成产生有害影响。通过这种方式获得的结果 第一阶段STTR赠款将深入了解AAV-RBD疗法在心血管疾病中的应用范围，并为后续大型动物研究的选择提供信息，以推进FDA的研究性新药申请。

 DESCRIPTION (provided by applicant): Pathological cardiac remodeling, including myocyte hypertrophy and apoptosis and myocardial interstitial fibrosis, constitutes a common pathway to heart failure in disease. Despite current pharmacologic therapy and other advances that attenuate remodeling, mortality due to heart failure remains high. New, more effective therapeutic options are desperately needed in an increasing patient population to improve both the survival and quality of life for patients with or susceptible to heart failure. We recently discovered that the protein kinase p90 ribosomal S6 kinase type 3 (RSK3) plays a critical role in the regulation of pathological cardiac remodeling. In 2013, Anchored RSK3 Inhibitors, LLC, was founded by Dr. Michael Kapiloff to develop novel therapeutics based upon RSK3 inhibition that will prevent and/or treat heart failure. RSK3 was required for pathological remodeling even though RSK3 is less abundant in the cardiac myocyte than other members of the RSK protein kinase family. We found that in myocytes RSK3's unique N- terminal domain conferred high affinity, regulated binding to the scaffold protein muscle A-kinase anchoring protein (mAKAPß). This novel protein-protein interaction explained the selective binding of that kinase isoform to the scaffold. New preliminary data show that expression both in vitro and in vivo of an anchoring disruptor peptide that blocks mAKAPß-RSK3 binding will attenuate pathological remodeling, preventing the development of heart failure in response to pressure overload. The goal of this STTR application is to support the development of a new adeno-associated virus (AAV) gene therapy vector that expresses the RSK3 anchoring disruptor peptide. The proposed research will provide proof-of-concept for a new therapeutic approach for the treatment and/or prevention of heart failure based upon RSK3 displacement within the myocyte. SPECIFIC AIM 1: Treatment of Pressure Overload-induced Heart Failure by Anchoring Disruptor Therapy. Cardiac myocyte-selective expression of a mAKAPß RSK3-binding peptide (RBD) using AAV prevents transverse aortic constriction-induced heart failure in vivo. In this Aim we will test whether RSK3 anchoring disruptor therapy can induce reverse remodeling and treat heart failure in mice with established pathology due to pressure overload. SPECIFIC AIM 2: Prevention of Myocardial Infarction-induced Heart Failure by Anchoring Disruptor Therapy. In this Aim, we will test whether AAV-RBD can block remodeling following myocardial infarction without having deleterious effects on infarct size or scar formation. Results obtained through this phase I STTR grant will provide insight into how broadly AAV-RBD therapy may be applied in cardiovascular disease and inform the choice of subsequent large animal studies necessary to progress to a FDA Investigational New Drug Application.