Gene Therapy with Cardiotropic Vectors for the Treatment of Heart Failure

描述（由申请人提供）：尽管有大量的治疗方法，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进程。由遗传或特殊情况引起的心衰，如冠状动脉疾病、高血压、糖尿病、感染或炎症，导致由替代纤维化、功能失调和正常肌细胞混合组成的异质心肌。保留的正常肌细胞处于激素和物理刺激的持续压力下，这些刺激可诱导细胞凋亡和细胞死亡或使其功能失调。因此，它们的保存是目前神经激素阻断疗法的目标。在了解心肌功能障碍的分子基础方面的最新进展，以及越来越有效的基因转移技术的发展，已经使一些心血管疾病的基因治疗成为可能。人类和实验HF的关键异常之一是肌浆网（SR）功能缺陷，这是细胞内Ca2+处理异常的原因。在人类和动物模型中，松弛期间SR Ca2+摄取不足已经在衰竭的心脏中被发现，并且与SR Ca2+- atp酶（SERCA2a）活性降低有关，这至少部分是由于磷蛋白（PLN）抑制增强。在心力衰竭的啮齿动物模型中，恢复SERCA2a水平或减少PLN抑制已被证明可以改善功能、代谢和/或生存率。最近，我们已经证明，通过在衰竭的心脏中组成性地激活蛋白磷酸酶1 （I-1）抑制剂，可以改善SR Ca2+处理，收缩性，最重要的是，通过直接减少纤维化和心脏肥厚，逆转不良重塑。因此，我们建议利用我们开发的用于心脏特异性基因转移的新载体直接靶向心脏I-1。这些新型的心向性载体，也被称为生物纳米颗粒（BNP），是基于重组腺相关病毒技术，表现出非常高的心向性。将这些新的心向性载体与一个重要的细胞内靶标结合起来，可能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. 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.