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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.