Advancing cBIN1 Therapy to Large Preclinical Animals

将 cBIN1 疗法推广至大型临床前动物

• 批准号: 10456878
• 负责人: TingTing Hong
• 金额: $ 22.88万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10456878
• 关键词: Acute; Adrenergic Agents; Affect; Age; Age-Years; Aging; American; Animal Model; Animals; Biochemical; Biological Markers; Blood; Budgets; Ca(2+)-Transporting ATPase; Calcium; Canis familiaris; Cardiac; Cardiac Myocytes; Cellular biology; Chronic; Clinical Trials; Congestive Heart Failure; Coupled; Coupling; Data; Dependovirus; Deterioration; Development; Diastole; Diastolic heart failure; Diffusion; Echocardiography; Edema; Electrons; Excision; Exclusion; Failure; Functional disorder; Goals; Heart; Heart Atrium; Heart failure; Hospitalization; Human; Ice; Image; Imaging Device; Impairment; Individual; Injections; Ions; L-Type Calcium Channels; Medicare; Medicine; Membrane; Membrane Microdomains; Methods; Modeling; Monitor; Morbidity - disease rate; Mus; Muscle; Muscle Cells; Myocardial; Myocardial dysfunction; Myocardium; Outcome; Pathologic; Patients; Physiology; Population; Proteins; Publishing; Recovery; Relaxation; Research; Resolution; Rodent; Rodent Model; Ryanodine Receptors; SERCA2a; Sarcoplasmic Reticulum; Surface; Symptoms; Syndrome; Tachycardia; Testing; Therapeutic; Time; Translating; Treatment Efficacy; Treatment Failure; United States; United States National Institutes of Health; Ventricular; Work; base; biochemical tools; canine model; cellular targeting; cost; efficacy study; extracellular; functional restoration; gene therapy; heart function; hemodynamics; improved; in vivo; mortality; novel; pre-clinical; pressure; recruit; reuptake; therapeutic target

Heart failure (HF) is a major cardiac syndrome with high mortality and morbidity which increases with age. For individuals 65 years of age and older, heart failure related hospitalization is the single greatest cost to the Medicare budget. In normal ventricular cardiomyocytes, beat-to-beat contraction and relaxation require coordinated systolic calcium release at dyads at transverse tubules (t-tubules, TT) and sarcoplasmic reticulum (SR) and diastolic calcium removal mainly through SR reuptake via Ca2+-ATPase (SERCA2a). A typical pathophysiology of failing cardiomyocytes is weakened calcium transients due to abnormal systolic calcium release from dyads as well as impaired diastolic removal due to altered SERCA2a activity. Central to the weakened transient is disorganization of TTs, their microdomains, and the calcium handling machinery. We recently identified that the calcium regulating cardiac bridging inte- grator 1 (cBIN1) forms TT microdomains and that cBIN1 is decreased in both systolic and diastolic HF. In rodent models, exogenous cBIN1 recovers failing myocardium. The overall objective here is to identify whether the cBIN1-microdomain targeting gene therapy can be translated from rodent studies to preclin- ical studies in a large animal model of HF. Our central hypothesis is that cBIN1-microdomains are dis- rupted in a canine model of chronic atrial pacing-induced HF, which can be rescued by exogenous cBIN1 gene therapy, allowing for recovery of failing myocardium. Two aims are proposed to first explore abnormal remodeling of subcellular microdomains in fail- ing cardiomyocytes from canine hearts subjected to tachy-pacing induced HF. Using biochemical and imaging tools, we will also determine the critical cellular point at which HF will require gene therapy. The second aim is proposed to study the efficacy of adeno associated virus 9 (AAV9)-transduced exog- enous cBIN1 in rescuing myocardial dysfunction and HF progression. A well-established canine model of chronic rapid atrial pacing-induced HF will be used to evaluate cardiomyocyte remodeling, functional deterioration, HF progression, as well as the therapeutic efficacy of intramyocardial injection of AAV9 transducing cBIN1 or a control protein GFP. Building on preliminary data, we will evaluate HF develop- ment by monitoring echocardiography recordings, hemodynamics, systemic symptoms, and blood available biomarkers. Our contribution here is expected to identify whether and how diminished cBIN1-microdomains are critical for reduced cardiac function in failing canine hearts, and whether exogenous cBIN1 can res- cue these hearts. The contribution is significant because it introduces a first in class HF therapeutic that targets the cellular remodeling of failing myocardium. Based on published and preliminary data, we ex- pect both a positive inotropic effect and lusitropic effect from exogenous cBIN1 therapy.

心力衰竭(HF)是一种主要的心脏综合征，具有很高的死亡率和发病率，并呈上升趋势。 随着年龄的增长。对于65岁及以上的人，与心力衰竭相关的住院治疗是唯一的 医疗保险预算的最大成本。在正常的心肌细胞中，搏动收缩和搏动 松弛需要在横管(T管，TT)的二联体协调收缩期钙释放。 肌浆网(SR)和舒张期钙的清除主要通过肌浆网通过钙-ATPase重摄取 (SERCA2a)。衰竭心肌细胞的典型病理生理学是由于 二尖瓣环收缩期钙释放异常，舒张期运动功能受损 SERCA2a活性。减弱的瞬变的核心是TT及其微域的无序化，以及 钙的搬运机械。我们最近发现，钙离子对心脏桥联的调节作用是通过细胞外信号转导途径实现的。 Grator 1(CBIN1)形成TT微区，cBIN1在收缩和舒张期HF均降低。 在啮齿动物模型中，外源性cBIN1可以恢复衰竭的心肌。这里的总体目标是确定 CBIN1-微域靶向基因治疗能否从啮齿动物研究转化为Preclin- 心衰大动物模型的临床研究。我们的中心假设是cBIN1-微域是分散的- 外源性cBIN1可挽救慢性心房起搏致心力衰竭犬模型 基因治疗，允许衰竭的心肌恢复。 首次提出了两个目标，以探索脑梗塞时亚细胞微域的异常重构。 犬心脏快速起搏诱发心力衰竭的心肌细胞。使用生化和 除了成像工具，我们还将确定HF需要基因治疗的关键细胞点。 第二个目的是研究腺相关病毒9型(AAV9)转导的外源病毒的疗效。 Enous cBIN1在抢救心肌功能不全和心力衰竭进展中的作用。一种成熟的犬类模型 慢性快速心房起搏诱发心力衰竭将用于评估心肌细胞重构、功能 心肌内注射AAV9对病情恶化、心力衰竭进展及疗效的影响 转导cBIN1或控制蛋白GFP。在初步数据的基础上，我们将评估高频开发- 通过监测超声心动图记录、血流动力学、全身症状和血液 可用的生物标志物。 我们的贡献有望确定cBIN1-微域是否以及如何减少 是衰竭犬心脏功能下降的关键因素，以及外源性cBIN1是否能- 暗示着这些心。这一贡献意义重大，因为它引入了一流的HF治疗方法 靶向衰竭心肌的细胞重塑。根据已公布的和初步的数据，我们之前- 预期外源性cBIN1治疗既有正性变力作用，又有正性变力作用。