Gene Therapy with Cardiotropic Vectors for the Treatment of Heart Failure

描述(由申请人提供)：尽管治疗方法激增，充血性心力衰竭(HF)仍是一种进展性疾病。血管紧张素转换酶抑制剂(ACEI)和b-受体阻滞剂的影响已经转化为更持久的益处，但许多患者在晚期疾病中对b-受体阻滞剂变得不耐受。因此，迫切需要创新而不是循序渐进的疗法来逆转心功能不全的进程。由遗传或特定条件引起的心衰，如冠状动脉疾病、高血压、糖尿病、感染或炎症，可导致由替代纤维化、功能障碍和正常心肌细胞组成的异质心肌。剩下的正常心肌细胞处于荷尔蒙和物理刺激的持续压力下，这些刺激可以诱导细胞凋亡和细胞死亡，或者使它们功能失调。因此，它们的保存是目前神经激素阻断治疗的目标。最近在了解心肌功能障碍的分子基础方面的进展，以及日益有效的基因转移技术的发展，使一些心血管疾病进入了基于基因的治疗的范围。肌浆网(SR)功能缺陷是人体和实验性心衰的主要异常之一，肌浆网功能缺陷是导致细胞内钙处理异常的原因。在人类和动物模型的衰竭心脏中，都发现在松弛过程中SR钙摄取不足，并与SR Ca~(2+)-ATPase(SERCA2a)活性降低有关，这至少部分是由于增强了磷蛋白(PLN)的抑制。恢复SERCA2a水平或减少PLN抑制已被证明可以改善心力衰竭啮齿动物模型的功能、代谢和/或存活率。最近，我们已经证明，通过在衰竭的心脏中结构性地激活蛋白磷酸酶1(I-1)的抑制物，可以改善SR对钙的处理，改善收缩能力，最重要的是，通过直接减少纤维化和心肌肥厚，逆转不利的重构。因此，我们建议利用我们开发的心脏特异性基因转移的新载体来直接靶向心脏I-1。这些新型的向心性载体，也被称为生物纳米颗粒(BNP)，是基于重组腺相关病毒技术，表现出非常高的心脏向向性。将这些新的心力性载体与一个重要的细胞内靶点相结合，可能会为心力衰竭的治疗提供一个新的范例。

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.