Gene Therapy with Cardiotropic Vectors for the Treatment of Heart Failure

心肌载体基因疗法治疗心力衰竭

• 批准号: 8197466
• 负责人: Roger J. Hajjar
• 金额: $ 41.95万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-01 至 2013-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8197466
• 关键词: Accounting; Adult; Angiotensin-Converting Enzyme Inhibitors; Animal Model; Apoptosis; Biological; Biological Preservation; Ca(2+)-Transporting ATPase; Calcium; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Cell Death; Cells; Clinical; Collaborations; Congestive Heart Failure; Coronary Arteriosclerosis; Defect; Development; Diabetes Mellitus; Disease; Effectiveness; Evolution; Exhibits; Experimental Models; Family suidae; Fibrosis; Gene Delivery; Gene Transfer; Genetic; Goals; Heart; Heart Hypertrophy; Heart failure; Hormonal; Human; Hypertension; Immunity; Individual; Infarction; Infection; Inflammation; Metabolism; Modeling; Molecular; Muscle Cells; Myocardial; Myocardial dysfunction; Myocardium; North Carolina; Patients; Phase I Clinical Trials; Phase II Clinical Trials; Progressive Disease; Proteins; Pump; Rattus; Recombinant adeno-associated virus (rAAV); Relaxation; Rodent Model; SERCA2a; Safety; Sarcoplasmic Reticulum; Serotyping; Signal Transduction; Somatic Gene Therapy; Staging; Stimulus; Stress; Technology; Testing; Translating; Tropism; Universities; Ventricular; Ventricular Dysfunction; adeno-associated viral vector; base; gene therapy; gene therapy clinical trial; gene transfer vector; hemodynamics; improved functioning; innovation; man; nanoparticle; neutralizing antibody; novel; phospholamban; programs; protein phosphatase inhibitor-1; public health relevance; sarcoplasmic reticulum calcium ATPase; transduction efficiency; uptake; vector

DESCRIPTION (provided by applicant): Despite the proliferation of therapies, congestive heart failure (HF) remains a progressive disease. The impact of angiotensin converting enzyme inhibitors (ACEI) and b-blockers has translated into more sustained benefit, but many patients become intolerant to b-blockers in late stage disease. There is therefore a desperate need for innovative rather than incremental therapies to reverse the course of ventricular dysfunction. HF induced by genetic or specific conditions, such as coronary artery disease, hypertension, diabetes, infection, or inflammation results in a heterogeneous myocardium consisting of a mixture of replacement fibrosis, dysfunctional and normal myocytes. The normal myocytes that remain are under continuous stress from hormonal and physical stimuli that can induce apoptosis and cell death or render them dysfunctional. Thus, their preservation is the target of current therapies with neurohormonal blockade. Recent advances in understanding the molecular basis of myocardial dysfunction, together with the evolution of increasingly efficient gene transfer technology, have placed some cardiovascular diseases within reach of gene-based therapies. One of the key abnormalities in both human and experimental HF is a defect in sarcoplasmic reticulum (SR) function, which is responsible for abnormal intracellular Ca2+ handling. Deficient SR Ca2+ uptake during relaxation has been identified in failing hearts from both humans and animal models and has been associated with a decrease in the activity of the SR Ca2+-ATPase (SERCA2a), which is at least partially due to enhanced phospholamban (PLN) inhibition. Restoring SERCA2a levels or reducing PLN inhibition has been shown to improve function, metabolism and/or survival in rodent models of heart failure. More recently, we have shown that by constitutively activating the inhibitor of protein phosphatase 1 (I-1) within the failing heart, there is improvement of SR Ca2+-handling, contractility and, most importantly, reversal of adverse remodeling by directly decreasing fibrosis and cardiac hypertrophy. We therefore propose to take advantage of novel vectors, which we have developed for cardiac specific gene transfer to directly target cardiac I-1. These novel cardiotropic vectors, which are also known as Bio Nano Particles (BNP), are based on recombinant adeno-associated virus technology which exhibit very high cardiac tropisms. Combining these novel cardiotropic vectors with an important intracellular target may provide a novel paradigm for the treatment of heart failure. PUBLIC HEALTH RELEVANCE: Over the last ten years, we have undertaken a program of targeting important calcium cycling proteins which has led to the first in man clinical trial of gene therapy for heart failure using adeno-associated type 1 (AAV) vector carrying the cardiac Sarcoplasmic Reticulum Calcium ATPase pump (SERCA2a). The use of AAV serotypes for gene delivery is limited in that they are not specific for the heart. We have developed a cardiotropic chimeric of AAV that specifically targets the heart and escapes the inherent immunity in patients and it is this new cardiotropic vector when combined with a novel well validated target that will offer a new paradigm for the treatment of heart failure.

描述（由申请人提供）：尽管治疗方法不断增加，但充血性心力衰竭（HF）仍然是一种进行性疾病。血管紧张素转换酶抑制剂（ACEI）和b受体阻滞剂的作用已转化为更持久的获益，但许多患者在疾病晚期对b受体阻滞剂不耐受。因此，迫切需要创新而不是增量疗法来逆转心室功能障碍的过程。由遗传或特定条件（例如冠状动脉疾病、高血压、糖尿病、感染或炎症）诱导的HF导致由替代纤维化、功能障碍和正常肌细胞的混合物组成的异质性心肌。剩下的正常肌细胞处于激素和物理刺激的持续压力下，这些刺激可以诱导凋亡和细胞死亡或使它们功能失调。因此，它们的保存是目前神经激素阻断疗法的目标。最近在了解心肌功能障碍的分子基础方面取得的进展，以及日益有效的基因转移技术的发展，使一些心血管疾病的基因治疗触手可及。在人类和实验HF中的关键异常之一是肌浆网（SR）功能的缺陷，其负责异常的细胞内Ca 2+处理。在来自人和动物模型的衰竭心脏中已经鉴定出松弛期间SR Ca 2+摄取不足，并且与SR Ca 2 +-ATP酶（SERCA 2a）的活性降低相关，这至少部分是由于受磷蛋白（PLN）抑制增强。恢复SERCA 2a水平或减少PLN抑制已显示改善心力衰竭啮齿动物模型中的功能、代谢和/或存活。最近，我们已经表明，通过组成性激活蛋白磷酸酶抑制剂1（I-1）在衰竭的心脏，有改善SR钙处理，收缩性，最重要的是，逆转不良重塑直接减少纤维化和心脏肥大。因此，我们建议利用新的载体，我们已经开发了心脏特异性基因转移直接靶向心脏I-1。这些新的亲心载体，也被称为生物纳米颗粒（BNP），是基于重组腺相关病毒技术，表现出非常高的亲心性。将这些新型的亲心性载体与重要的细胞内靶点相结合可能为心力衰竭的治疗提供新的范例。 公共卫生关系：在过去的十年中，我们已经开展了一项针对重要的钙循环蛋白的计划，这导致了使用携带心脏肌浆网钙ATP酶泵（SERCA 2a）的腺相关1型（AAV）载体进行心力衰竭基因治疗的首次人体临床试验。AAV血清型用于基因递送的用途是有限的，因为它们对心脏不是特异性的。我们已经开发了一种AAV的亲心嵌合体，其特异性靶向心脏并逃避患者的固有免疫，并且当与新的充分验证的靶标组合时，这种新的亲心载体将为心力衰竭的治疗提供新的范例。