PP2A Anchoring Disruptor Therapy in Heart Failure

PP2A 锚定破坏器治疗心力衰竭

基本信息

批准号：
10323602
负责人：
Federico Cividini
金额：
$ 43.69万
依托单位：
CARDIAC RSK3 INHIBITORS, LLC
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10323602
关键词：
A kinase anchoring protein American Animal Model Animals Attenuated Binding Binding Proteins Biological Blood Circulation Canis familiaris Cardiac Cardiac Myocytes Cardiovascular Diseases Catheterization Cessation of life Clinical Trials Complex Data Dependovirus Diagnosis Dilated Cardiomyopathy Disease Dose EFRAC Echocardiography Family suidae Fibrosis Gene Transduction Agent Growth Heart Heart failure Histologic Holoenzymes Human Hypertrophy Infusion procedures Intervention Ischemia Laboratories Left Left Ventricular Ejection Fraction Left ventricular structure Legal patent Length Magnetic Resonance Imaging Mediating Molecular Analysis Morbidity - disease rate Mus Muscle Muscle Cells Muscle Proteins Myocardial Infarction Myocardial Ischemia PPP2R5D gene Pathologic Pathway interactions Patients Peptides Pharmacology Phase Phosphorylation Physiologic intraventricular pressure Prevention Prevention approach Procedures Protein Binding Domain Protein Dephosphorylation Protein Inhibition Protein Phosphatase 2A Regulatory Subunit PR53 Protein phosphatase Public Health Publishing Quality of life Reperfusion Therapy Research Safety Scaffolding Protein Serine Serotyping Serum Response Factor Signal Transduction Small Business Innovation Research Grant Stroke Volume Structure Syndrome Tertiary Protein Structure Testing Tissues Toxicology Troponin T Universities Ventricular Ventricular End-Systolic Volumes Width Work adeno-associated viral vector base cellular pathology clinically relevant efficacy study efficacy testing first-in-human gene therapy heart function heart preservation hemodynamics improved inhibitor/antagonist ischemic cardiomyopathy molecular pathology mortality novel strategies novel therapeutic intervention novel therapeutics patient population porcine model preservation prevent primary endpoint promoter protein B protein protein interaction restoration secondary endpoint therapeutic target vector

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, morbidity and mortality due to heart failure remain high. Novel therapeutic approaches are desperately needed in an expanding patient population to improve both the survival and quality of life for patients with or susceptible to heart failure. Research over the last two decades, mainly in the academic laboratory of Dr. Michael S. Kapiloff, has established the 230 kDa scaffold protein muscle A-kinase anchoring protein β (mAKAPβ) as the organizer of multimolecular signaling complexes critical in the cardiac myocyte for the induction and progression of pathological cardiac remodeling. One constituent of mAKAPβ “signalosomes” is protein phosphatase 2A (PP2A) that contains the B56δ (PPP2R5D) regulatory subunit. New preliminary data show that mAKAPβ-bound PP2A regulates myocyte elongation and ventricular dilation in disease. Observations that B56δ expression is elevated in human and canine heart failure support the candidacy of mAKAPβ-bound PP2A as a target for intervention in the treatment of non-ischemic and ischemic dilated cardiomyopathies. Cardiac RSK3 Inhibitors, LLC (CRI Biotech) is a company founded by Dr. Kapiloff that is developing patent-protected therapeutics targeting cardiac myocyte mAKAPβ signalosomes for the prevention and/or treatment of heart failure. To target mAKAPβ-PP2A complexes via blockade of PP2A-mAKAPβ protein-protein interaction, CRI Biotech is developing a new self-complementary, adeno-associated virus serotype 9 (AAV9sc) gene therapy vector. Preliminary data in mice shows that treatment with this vector results in restoration and long term preservation of cardiac structure and function following myocardial infarction. CRI Biotech proposes that this gene therapy constitutes a novel approach for the prevention and/or treatment of pathological ventricular dilation and eccentric hypertrophy, with potentially broad efficacy across diverse cardiovascular diseases. In this Fast-Track SBIR application, CRI Biotech will test the efficacy of the new biologic in a clinically relevant swine model of ischemic cardiomyopathy, as a pivotal efficacy study and key step on the path to first-in-human clinical trials. Phase I - The milestone for this Aim is the determination of the minimum AAV9sc dose required for consistent inhibition of PP2A anchoring to mAKAPβ in the heart, thereby defining the appropriate biologic dose to be used for efficacy testing in Phase II. Phase II - Specific Aim 1: Efficacy of the new gene therapy for post-myocardial infarction heart failure in a large animal model. The core of this project is to test whether the new AAV9sc-based gene therapy will reduce pathological remodeling induced by MI in swine, preventing heart failure. Specific Aim 2: Taking advantage of tissue collected from the same animals used in Aim 1, the benefits of the new gene therapy will be further demonstrated by gravimetric, histological, and molecular analyses.

病理性心脏重塑构成疾病中心力衰竭的常见途径。当前的药物治疗和其他进展可减轻由于重塑、发病率和死亡率不断扩大的患者迫切需要新的治疗方法。改善心力衰竭患者或易患心力衰竭患者的生存率和生活质量。在过去的二十年里，主要在 Michael S. Kapiloff 博士的学术实验室中，建立了 230 kDa 支架蛋白肌 A 激酶锚定蛋白 β (mAKAPβ) 作为多分子信号传导的组织者心肌细胞中对于病理性心脏重塑的诱导和进展至关重要的复合物。 mAKAPβ“信号体”的一种成分是蛋白磷酸酶 2A (PP2A)，其中含有 B56δ (PPP2R5D) 调节亚基新的初步数据表明 mAKAPβ 结合的 PP2A 调节肌细胞。疾病中 B56δ 表达升高的观察结果。犬心力衰竭支持 mAKAPβ 结合 PP2A 作为治疗干预靶标的候选资格非缺血性和缺血性扩张型心肌病的 RSK3 Inhibitors, LLC (CRI Biotech) 是一家。由 Kapiloff 博士创立的公司，正在开发针对心肌细胞的受专利保护的疗法用于预防和/或治疗心力衰竭的 mAKAPβ 信号体靶向 mAKAPβ-PP2A 复合物。通过阻断 PP2A-mAKAPβ 蛋白质-蛋白质相互作用，CRI Biotech 正在开发一种新的自我互补、腺相关病毒血清型 9 (AAV9sc) 基因治疗载体在小鼠中的初步数据显示治疗效果。使用该载体可以恢复并长期保存心脏结构和功能 CRI Biotech 提出，这种基因疗法是治疗心肌梗塞的一种新方法。预防和/或治疗病理性心室扩张和离心性肥大，具有潜在的广泛用途在这个快速 SBIR 应用中，CRI Biotech 将测试该药物在多种心血管疾病中的功效。新生物制剂在临床相关猪缺血性心肌病模型中的功效，作为关键功效研究和首次人体临床试验道路上的关键一步 - 这一目标的里程碑是。确定持续抑制锚定于 mAKAPβ 的 PP2A 所需的最小 AAV9sc 剂量心脏，从而确定用于 II 期功效测试的适当生物剂量。具体目标 1：新基因疗法对大型动物心肌梗死后心力衰竭的疗效该模型的核心是测试基于AAV9sc的新基因疗法是否会减少病理。猪心肌梗死诱导的重塑，预防心力衰竭具体目标 2：利用收集的组织。来自目标 1 中使用的相同动物，新基因疗法的益处将通过重量分析、组织学和分子分析。