PP2A Anchoring Disruptor Therapy in Heart Failure

PP2A 锚定破坏器治疗心力衰竭

• 批准号: 10510778
• 负责人: Federico Cividini
• 金额: $ 188.88万
• 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 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10510778
• 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; Echocardiography; Family suidae; Fibrosis; Gene Transduction Agent; Heart; Heart failure; Histologic; Human; Hypertrophy; Infusion procedures; Intervention; Ischemia; Laboratories; Left; Left Ventricular Ejection Fraction; 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 Inhibition; Protein Phosphatase 2A Regulatory Subunit PR53; Protein phosphatase; Public Health; Publishing; Quality of life; Reperfusion Therapy; Research; Safety; Scaffolding Protein; 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; 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; 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，减轻重塑，发病率和死亡率， 心力衰竭仍然很高。新的治疗方法是迫切需要在一个扩大的病人 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。研究 在过去的二十年里，主要是在迈克尔·S·卡皮洛夫，建立了230个 kDa支架蛋白肌肉A激酶锚定蛋白β（mAKAPβ）作为多分子信号传导的组织者 在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（PP 2A），其含有B56δ （PPP 2 R5 D）调节亚基。新的初步数据显示mAKAPβ结合的PP 2A调节肌细胞 延长和心室扩张。观察到B56δ表达在人类和哺乳动物中升高， 犬心力衰竭支持mAKAPβ结合PP 2A作为治疗干预靶点的候选资格 非缺血性和缺血性扩张型心肌病的区别Cardiac RSK 3 Inhibitors，LLC（CRI Biotech）是一家 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-PP 2A复合物 通过阻断PP 2A-mAKAP β蛋白-蛋白相互作用，CRI Biotech正在开发一种新的自我互补， 腺相关病毒血清型9（AAV 9 sc）基因治疗载体。小鼠的初步数据显示， 使用该载体导致心脏结构和功能的恢复和长期保存， 心肌梗死CRI生物技术公司提出，这种基因治疗构成了一种新的方法， 预防和/或治疗病理性心室扩张和离心性肥大， 对多种心血管疾病的疗效。在这个快速通道SBIR应用中，CRI Biotech将测试 新生物制剂在缺血性心肌病临床相关猪模型中的疗效，作为关键疗效 这是首次人体临床试验的关键一步。第一阶段-这一目标的里程碑是 确定在细胞中PP 2A锚定至mAKAPβ的一致抑制所需的最小AAV 9 sc剂量 心脏，从而确定用于II期疗效试验的适当生物剂量。第二阶段- 具体目标1：新基因治疗对大型动物心肌梗死后心力衰竭的疗效 模型该项目的核心是测试新的基于AAV 9 sc的基因治疗是否会减少病理性 在猪中由MI诱导的重构，预防心力衰竭。具体目标2：利用收集的组织 从目标1中使用的相同动物中，新基因疗法的益处将进一步得到证明， 重量分析、组织学和分子分析。