RSK3 Anchoring Disruptor Therapy for Heart Failure

RSK3 锚定破坏器治疗心力衰竭

基本信息

批准号：
8977557
负责人：
Michael Seth Kapiloff
金额：
$ 29.9万
依托单位：
ANCHORED RSK3 INHIBITORS, LLC
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-01 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8977557
关键词：
3-Phosphoinositide Dependent Protein Kinase-1 A kinase anchoring protein Affinity American Animal Model Animals Aortic Valve Stenosis Apoptosis Attenuated Binding Biological Products Cardiac Cardiac Myocytes Cardiovascular Diseases Cause of Death Cell Nucleus Cessation of life Cicatrix Clinical Coronary Arteriosclerosis Coronary artery Cytosol Data Dependovirus Development Diagnosis Disease Enzymes Etiology Family Fibrosis Functional disorder Future Gene Expression Gene Transduction Agent Genetic Models Goals Grant Growth Heart Heart failure Hypertension Hypertrophy In Vitro Infarction Infusion procedures Investigational New Drug Application Knock-out Left Ligation MEKKs MEKs Modeling Mus Muscle Muscle Cells Myocardial Myocardial Infarction N-terminal Nuclear Pathology Pathway interactions Patients Peptides Phase Phosphatidylinositols Phosphorylation Phosphotransferases Play Prevention Protein Isoforms Protein Kinase Quality of life RPS6KA gene Regulation Research Ribosomal Protein S6 Kinase Role Scaffolding Protein Signal Pathway Signal Transduction Small Business Technology Transfer Research Specificity Stress Syndrome Tertiary Protein Structure Testing Therapeutic base commercialization common treatment constriction improved in vivo inhibitor/antagonist insight interstitial member mortality novel novel therapeutic intervention novel therapeutics patient population pressure prevent protein protein interaction public health relevance response scaffold selective expression

项目摘要

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.

描述（由适用提供）：病理心脏重塑，包括心肌肥大和凋亡和心肌间质纤维化，构成了疾病心力衰竭的常见途径。尽管目前的药理疗法和其他减弱重塑的进展，但由于心力衰竭而导致的死亡率仍然很高。在越来越多的患者人群中，迫切需要新的，更有效的治疗选择，以改善患有或容易患心力衰竭的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型（RSK3）在病理心脏重塑的调节中起关键作用。 2013年，Michael Kapiloff博士建立了锚定的RSK3抑制剂LLC，以基于RSK3抑制作用来开发新的疗法，以预防和/或治疗心力衰竭。即使RSK3在心肌细胞中的RSK3比RSK蛋白激酶家族的其他成员中的RSK3较少，RSK3也需要病理重塑。我们发现，在肌细胞中，RSK3独特的N末端结构域赋予了高亲和力，调节了与脚手架蛋白肌肉A-激酶锚定蛋白（Makapß）的结合。这种新型的蛋白质蛋白相互作用解释了该激酶同工型与支架的选择性结合。新的初步数据表明，在体外和体内表达锚定肽肽的体内表达，该肽会阻断makapß-rsk3结合将减弱病理重塑，从而阻止对压力超负荷的响应心力衰竭的发展。该STTR应用的目的是支持开发新的与腺相关病毒（AAV）基因疗法载体，该病毒表达了RSK3锚定破坏者肽。拟议的研究将为基于心肌内RSK3位移的治疗和/或预防心力衰竭的新治疗方法提供概念验证。特定目标1：通过锚定破坏者治疗来治疗压力超负荷引起的心力衰竭。使用AAV的MakapßRSK3结合肽（RBD）的心肌细胞选择性表达可防止横向主动脉收缩诱导的体内心力衰竭。在此目标中，我们将测试RSK3锚定扰动疗法是否可以诱导反向重塑和治疗由于压力超负荷而既定病理学的小鼠的心力衰竭。特定目标2：通过锚定破坏者治疗来预防心肌违规引起的心力衰竭。在此目标中，我们将测试AAV-RBD是否可以阻止心肌违规后的重塑，而不会对梗塞大小或疤痕形成产生有害影响。通过此获得的结果 I期STTR赠款将提供有关如何将AAV-RBD疗法应用于心血管疾病中的广泛性，并为随后的大型动物研究的选择提供了进展，以进行FDA研究新药应用所需的大型动物研究。