PP2A Anchoring Disruptor Therapy in Heart Failure

PP2A 锚定破坏器治疗心力衰竭

• 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
• 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

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.

病理性心脏重塑是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，以减轻因高血压引起的重塑、发病率和死亡率 心力衰竭仍居高不下。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和生活质量。研究 在过去的二十年里，主要是在迈克尔·S·卡皮洛夫博士的学术实验室里，已经建立了230 作为多分子信号组织者的Kda支架蛋白肌肉A-激酶锚定蛋白β(β) 心肌细胞中对病理性心脏重塑的诱导和进展至关重要的复合体。 MAKAPβ信号小体的一个组成成分是含有B56δ的蛋白磷酸酶2A (PPP2R5D)调节亚基。新的初步数据显示，mAKAPβ结合的PP2A调节心肌细胞 疾病中的延长和脑室扩张。观察到B56δ在人类和 犬心力衰竭支持mAKAPβ结合的PP2A作为干预治疗的靶点 非缺血型和缺血型扩张型心肌病。心脏RSK3抑制剂，LLC(CRI Biotech)是一种 由Kapiloff博士创立的公司，正在开发针对心肌细胞的专利保护疗法 用于预防和/或治疗心力衰竭的mAKAPβ信号体。靶向mAKAPβ-PP2A复合体 通过阻断PP2A-mAKAPβ蛋白质之间的相互作用，华润生物技术正在开发一种新的自我互补的， 腺相关病毒血清型AAV9sc基因治疗载体。在老鼠身上的初步数据表明，治疗 使用该载体后心脏结构和功能的恢复和长期保存 心肌梗死。CRI Biotech提出，这种基因疗法构成了一种新的治疗方法 预防和/或治疗病理性心室扩张和离心性肥厚，具有潜在的广泛 对各种心血管疾病的疗效。在这个Fast-Track SBIR应用中，CRI Biotech将测试 作为关键疗效的新生物制剂在临床相关的猪缺血性心肌病模型中的疗效 研究和迈向首个人类临床试验的关键步骤。第一阶段--这一目标的里程碑是 持续抑制PP2A锚定mAKAPβ所需AAV9sc最小剂量的确定 从而确定用于第二阶段有效性测试的适当生物剂量。第二阶段- 具体目标1：新基因疗法对大动物心肌梗死后心力衰竭的疗效 模特。这个项目的核心是测试基于AAV9sc的新基因疗法是否会减少病理 心肌梗死诱发猪心脏重塑，预防心力衰竭。具体目标2：利用收集到的组织 在AIM 1中使用的相同动物中，新基因疗法的好处将通过以下方式进一步证明 重量分析、组织学和分子分析。