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ShRNA-Based Targeting of mAKAPÎ² in Heart Failure

基于 ShRNA 的 mAKAP™ 靶向治疗心力衰竭

基本信息

批准号：
10403585
负责人：
Federico Cividini
金额：
$ 88.5万
依托单位：
CARDIAC RSK3 INHIBITORS, LLC
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10403585
关键词：
3-Phosphoinositide Dependent Protein Kinase-1 A kinase anchoring protein American Animal Model Animals Attenuated Binding Biological Calcineurin Cardiac Cardiac Myocytes Cardiovascular Diseases Cardiovascular Models Catheterization Cause of Death Cell Nucleus Chickens Chronic Clinical Trials Complex Conserved Sequence Cyclic AMP Cyclic AMP-Dependent Protein Kinases Cytosol Data Dependovirus Development Diagnosis Disease Dose Echocardiography Family suidae Fibrosis Gene Expression Gene Transduction Agent Goals HDAC4 gene Heart Heart failure Histologic Histone Deacetylase Hypoxia Infusion procedures Ischemia Knock-out Laboratories Left Left Ventricular Ejection Fraction Legal patent MEKs Mediating Messenger RNA Mitogen-Activated Protein Kinases Molecular Analysis Mus Muscle Muscle Proteins Myocardial Infarction PDE4D3 Pathologic Pathway interactions Patients Pharmacology Phase Phosphatidylinositols Phosphorylation Physiologic intraventricular pressure Play Prevention Procedures Protein Kinase Pulmonary Edema Quality of life RNA Interference Reperfusion Therapy Research Rodent Role Safety Scaffolding Protein Serotyping Signal Transduction Signaling Molecule Site Small Business Innovation Research Grant Stimulus Stress Stroke Volume Structure Syndrome Testing Therapeutic Tissues Toxicology Translating Troponin T Ventricular End-Systolic Volumes base cardiogenesis cellular pathology clinically relevant conditional knockout design efficacy testing first-in-human heart preservation hemodynamics improved improved outcome inhibitor man molecular pathology mortality novel novel therapeutics patient population preservation pressure prevent primary endpoint promoter protein B protein kinase D response secondary endpoint selective expression small hairpin RNA therapeutically effective transcription factor translational pipeline

项目摘要

Pathological cardiac remodeling 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. Muscle A-kinase anchoring protein β (mAKAPβ) is the organizer of multimolecular signaling complexes critical for the induction and progression of pathological cardiac remodeling. By binding a diverse set of signaling molecules, mAKAPβ dynamically orchestrates multiple signaling modules that transduce cAMP, mitogen-activated protein kinase (MAPK), Ca2+, phosphoinositide, and hypoxic stress signals. Accordingly, cardiomyocyte-specific mAKAPβ knock-out in mice inhibited remodeling and the development heart failure in multiple models of cardiovascular disease. CRI is a company developing novel, patent protected therapeutics for the prevention and/or treatment of heart failure. In this Fast-Tract SBIR, CRI will test a new gene therapy vector designed to inhibit mAKAPβ expression selectively in the cardiac myocyte by RNA interference. The AAV9sc.shmAKAP biologic is a self- complementary, cardiotropic, serotype 9 adeno-associated virus (AAV9) that expresses an mAKAP-specific small hairpin RNA (shRNA) under the control of a cardiac myocyte-specific promoter. In this application, CRI will test the new biologic in a clinically relevant large animal model for post-myocardial infarction (MI) heart failure. Phase I - Specific Aim: We will perform a dose response curve for the biologic in Yorkshire swine to determine the minimum dose required for consistent inhibition of mAKAPβ expression in the heart. Phase II - Specific Aim 1: Efficacy of mAKAP RNAi for heart failure in a large animal model. The core of this project is to test whether mAKAPβ RNAi will mitigate pathological remodeling induced by MI in swine, preventing heart failure. Swine will be subjected to ischemia-reperfusion to induce MI or sham procedure and then treated with the AAV9sc.shmAKAP biologic by intracoronary infusion immediately after or 1 month later at the dose determined in Phase I. The pigs will be followed by serial echocardiography and studied at endpoint 3 months post-MI by catheterization for left ventricular pressure-volume loop hemodynamics. The goal for this Aim is the demonstration that mAKAP RNAi will preserve cardiac structure and function in a large animal model of MI disease. Specific Aim 2: AAV9sc.shmAKAP-mediated inhibition of the molecular and cellular pathology associated with heart failure. Taking advantage of tissue collected from the same animals used in Aim 1, the benefits of mAKAP RNAi in swine will be demonstrated by gravimetric, histological, and molecular analyses for fibrosis and other markers of cardiac remodeling and heart failure. In addition, initial toxicology screens will be done to support the biologic’s safety. This project will show that mAKAPβ targeting is a viable therapeutic strategy for heart failure post-MI and justify a first-in-human clinical trial for heart failure.

病理性心脏重塑构成疾病中心力衰竭的常见途径。尽管目前药物治疗和其他减轻重构的进展，心力衰竭引起的死亡率仍然存在高的。越来越多的患者迫切需要新的、更有效的治疗方案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。肌肉A激酶锚定蛋白 β (mAKAPβ) 是多分子信号复合物的组织者，对于诱导至关重要和病理性心脏重塑的进展。通过结合多种信号分子，mAKAPβ 动态协调转导 cAMP（丝裂原激活蛋白激酶）的多个信号模块 (MAPK)、Ca2+、磷酸肌醇和缺氧应激信号。因此，心肌细胞特异性 mAKAPβ 小鼠基因敲除可抑制多种心血管模型的重塑和心力衰竭的发展疾病。 CRI 是一家开发新型、受专利保护的治疗方法的公司，用于预防和/或治疗心力衰竭。在本次 Fast-Tract SBIR 中，CRI 将测试一种旨在抑制 mAKAPβ 的新基因治疗载体通过RNA干扰在心肌细胞中选择性表达。 AAV9sc.shmAKAP 生物制剂是一种自互补、心肌、血清型 9 腺相关病毒 (AAV9)，表达 mAKAP 特异性心肌细胞特异性启动子控制下的小发夹 RNA (shRNA)。在此应用中，CRI 将在临床相关的大型动物模型中测试这种新生物制剂治疗心肌梗塞后心力衰竭的效果。第一阶段 - 具体目标：我们将在约克郡猪中绘制生物制剂的剂量反应曲线，以确定持续抑制心脏中 mAKAPβ 表达所需的最小剂量。第二阶段 - 具体目标图 1：mAKAP RNAi 在大型动物模型中对心力衰竭的功效。这个项目的核心是测试 mAKAPβ RNAi 是否会减轻猪 MI 诱导的病理重塑，预防心力衰竭。对猪进行缺血再灌注以诱导心肌梗死或假手术，然后用 AAV9sc.shmAKAP 生物制品，按确定剂量后立即或 1 个月后通过冠状动脉内输注在第一阶段。这些猪将接受连续超声心动图检查，并在 MI 后 3 个月的终点进行研究插管检查左心室压力-容量环血流动力学。该目标的目标是证明 mAKAP RNAi 将在大型 MI 动物模型中保留心脏结构和功能疾病。具体目标 2：AAV9sc.shmAKAP 介导的分子和细胞病理抑制与心力衰竭有关。利用从目标 1 中使用的相同动物收集的组织， mAKAP RNAi 对猪的益处将通过重量分析、组织学和分子分析来证明纤维化以及心脏重塑和心力衰竭的其他标志物。此外，初步毒理学筛查将这样做是为了支持生物制剂的安全性。该项目将表明 mAKAPβ 靶向是一种可行的治疗策略治疗心肌梗死后心力衰竭，并证明首次人体心力衰竭临床试验的合理性。