Advancing cBIN1 Therapy to Large Preclinical Animals

将 cBIN1 疗法推广至大型临床前动物

• 批准号: 10317539
• 负责人: TingTing Hong
• 金额: $ 19.06万
• 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/10317539
• 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; 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，具有高死亡率和高发病率， 随年龄对于65岁及以上的个体，心力衰竭相关的住院是唯一的 医疗预算的最大成本。在正常的心室肌细胞中， 舒张需要在横小管（t-小管，TT）的二分体处协调收缩期钙释放， 肌浆网（SR）和舒张期钙清除主要通过SR再摄取通过Ca 2 +-ATP酶 （SERCA2a）。衰竭的心肌细胞的典型病理生理学是由于以下原因而减弱的钙瞬变： 二分体的收缩期钙释放异常，以及由于改变的 SERCA 2a活性。减弱瞬变的核心是TT、它们的微域和它们的微结构的解体。 钙处理机械我们最近发现，钙调节心脏桥接， grator 1（cBIN 1）形成TT微区，cBIN 1在收缩期和舒张期HF中均降低。 在啮齿动物模型中，外源性cBIN 1恢复衰竭的心肌。这里的总体目标是确定 cBIN 1-微结构域靶向基因治疗是否可以从啮齿动物研究转化为preclin- 在HF的大型动物模型中的临床研究。我们的中心假设是，cBIN 1-微域是dis-peptide- 在慢性心房起搏诱导的HF犬模型中破裂，可通过外源性cBIN 1挽救 基因治疗，使衰竭的心肌得以恢复。 提出两个目标，首先探索亚细胞微区的异常重塑失败， 从经受快速起搏诱导的HF的犬心脏中培养心肌细胞。利用生物化学和 通过使用成像工具，我们还将确定HF需要基因治疗的关键细胞点。 提出第二个目的是研究腺相关病毒9（AAV 9）转导的exog的功效。 静脉cBIN 1在挽救心肌功能不全和HF进展中的作用一个成熟的犬类模型 慢性快速心房起搏诱导的HF将用于评估心肌细胞重塑，功能 恶化、HF进展以及心肌内注射AAV 9的治疗功效 转导cBIN 1或对照蛋白GFP。在初步数据的基础上，我们将评估HF的发展- 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。 我们在这里的贡献，预计将确定是否以及如何减少cBIN 1-微域 对于衰竭犬心脏的心脏功能降低至关重要，以及外源性cBIN 1是否可以恢复心脏功能。 提示这些红心这一贡献是重要的，因为它引入了一流的HF治疗， 靶向衰竭心肌的细胞重塑。根据已公布的数据和初步数据，我们认为， 预期外源性cBIN 1治疗具有正性肌力作用和负性肌力作用。