RSK3 Anchoring Disruptor Therapy for Heart Failure

 描述（由申请人提供）：病理性心脏重塑，包括肌细胞肥大和凋亡以及心肌间质纤维化，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进展，削弱重塑，由于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、更有效的治疗选择，以提高心力衰竭患者或易患心力衰竭患者的生存率和生活质量。我们最近发现蛋白激酶p90核糖体S6激酶3（RSK 3）在病理性心脏重塑的调节中起着关键作用。2013年，Anchored RSK 3 Inhibitors，LLC由Michael Kapiloff博士创立，旨在开发基于RSK 3抑制的新型疗法，以预防和/或治疗心力衰竭。RSK 3是病理性重塑所必需的，尽管RSK 3在心肌细胞中的丰度低于RSK蛋白激酶家族的其他成员。我们发现，在肌细胞中，RSK 3的独特的N-末端结构域赋予了与支架蛋白肌肉A-激酶锚定蛋白（mAKAP）的高亲和力、调节性结合。这种新的蛋白质-蛋白质相互作用解释了该激酶同种型与支架的选择性结合。新的初步数据表明，在体外和体内表达的锚定干扰肽，阻断mAKAP蛋白-RSK 3结合将减弱病理性重塑，防止心力衰竭的发展，在压力超负荷。该STTR应用的目标是支持表达RSK 3锚定破坏肽的新型腺相关病毒（AAV）基因治疗载体的开发。拟议的研究将提供一种新的治疗方法的概念验证，用于治疗和/或预防基于肌细胞内RSK 3置换的心力衰竭。具体目标1：通过干扰素治疗治疗压力超负荷引起的心力衰竭。心肌细胞选择性表达mAKAPRSK 3结合肽（RBD）使用AAV预防体内横向主动脉缩窄诱导的心力衰竭。在这个目标中，我们将测试RSK 3锚定破坏剂疗法是否可以诱导逆转重构并治疗具有由于压力超负荷而建立的病理学的小鼠的心力衰竭。特定目的2：通过干扰素治疗预防心肌缺血诱导的心力衰竭。在这个目标中，我们将测试AAV-RBD是否可以阻断心肌梗死后的重构而不对梗死面积或瘢痕形成产生有害影响。通过此获得的结果 第一阶段STTR拨款将提供对AAV-RBD疗法在心血管疾病中的广泛应用的深入了解，并为后续大型动物研究的选择提供信息，这些研究是FDA研究性新药申请所必需的。

 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.