C-TRIP: Targeted Gene Therapy for the Treatment of Heart Failure (P20)

描述（由申请人提供）： 尽管治疗方法不断增多，但充血性心力衰竭（HF）仍然是一种进行性疾病。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。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HF进入了基于基因的治疗范围。人和实验性HF中的关键细胞改变之一是肌浆网（SR）功能的缺陷，其负责在衰竭心肌细胞中观察到的异常细胞内Ca 2+处理1 -4松弛期间SR Ca 2+摄取的缺陷已经在来自人和动物模型的衰竭心脏中被鉴定并且与SR Ca 2 +-ATP酶（SERCA 2a）活性的降低相关，这至少部分是由于增强的受磷蛋白（PLN）抑制。恢复SERCA 2a水平或减少PLN抑制已显示在许多心力衰竭实验模型中改善功能、代谢和/或存活。在过去的十年中，我们已经开始并最近完成了第一次在人1期临床试验的基因治疗心力衰竭使用腺相关1型（AAV）载体携带SERCA 2a 5。AAV基因治疗的安全性特征沿着从该1期试验获得的阳性生物信号，导致在NYHA III/IV级患者中启动AAV1.SERCA2a的2期试验6。最近，我们已经表明，通过组成性激活衰竭心脏内的蛋白磷酸酶1（1 -1）的抑制剂，SR Ca 2+处理、收缩性得到改善，并且最重要的是，通过直接减少纤维化和心脏肥大逆转不良重塑7 -13。尽管AAV载体已在包括心力衰竭患者在内的多项试验中被证明是安全的，但其用于基因递送具有以下限制：1）它们对心脏不是特异性的，以及2）针对任何个体血清型的先前中和抗体占这些患者的40%，这些患者需要从临床试验中排除14 -17。因此，我们开发了一种AAV的亲心嵌合体，其更特异性地靶向心脏并逃避患者的固有免疫。因此，我们建议利用这些新的嵌合载体，也称为生物纳米颗粒（BNP），在心力衰竭的实验模型中直接靶向I-1 14 -17。在该提案的第1阶段，我们将在心力衰竭的临床前模型中使用这种新型载体验证靶标。此外，我们将分析心力衰竭患者人群中针对我们新的亲心载体的既存中和抗体的患病率。在第2阶段，我们将在心力衰竭患者中进行通过冠状动脉内输注BNP 111.sc-CMV. llc的I期、开放标签、剂量递增试验，随后在心力衰竭患者中进行BNP 111.sc-CMV. llc的冠状动脉内输注的II期、随机、双盲、安慰剂对照剂量递增试验。 相关性（参见说明）：心力衰竭是美国发病率和死亡率的主要原因，尽管用于治疗这些患者的新疗法。基因治疗已成为一种新的和可行的战略，以针对特定的异常，在衰竭的心脏。我们已经开发了一种亲心脏的腺相关载体（AAV），其特异性靶向心脏并逃避患者的固有免疫。这种新的亲心载体与新的经过充分验证的靶点相结合，为心力衰竭的治疗提供了一种新的策略。

DESCRIPTION (provided by applicant): Despite the proliferation of therapies, congestive heart failure (HF) remains a progressive disease. There is therefore a desperate need for innovative rather than incremental therapies to reverse the course of ventricular dysfunction. Recent advances in understanding the molecular basis of myocardial dysfunction, together with the evolution of increasingly efficient gene transfer technology, have placed HF within reach of gene-based therapies. One of the key cellular alterations in both human and experimental HF is a defect in sarcoplasmic reticulum (SR) function, which is responsible for the abnormal intracellular Ca2+ handling observed in failing cardiomyocytes1-4 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 a number of experimental models of heart failure. Over the last ten years, we have initiated and recently completed a first-in-man phase 1 clinical trial of gene therapy for heart failure using adeno-associated type 1 (AAV) vector carrying SERCA 2a5. The safety profile of AAV gene therapy along with the positive biological signals obtained from this phase 1 trial has led to the initiation of a phase 2 trial of AAV1.SERCA2a in NYHA class III/IV patients6. More recently, we have shown that by constitutively activating the inhibitor of protein phosphatase 1 (l-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 hypertrophy7-13. Even though AAV vectors have been proven to be safe in multiple trials including in patients with heart failure, their use for gene delivery has the following limitations: 1) they are not specific for the heart and 2) antecedent neutralizing antibodies to any individual serotype account for 40% of these patients which would need to be excluded from clinical trials14-17. We have therefore developed a cardiotropic chimeric of AAV that targets more specifically the heart and escapes the inherent immunity in patients. We, therefore, propose to take advantage of these novel chimeric vectors, which are also known as Bio Nano Particles (BNP), to directly target I-1 in experimental models of heart failure14-17. Within STAGE 1 of this proposal we will validate the target using this novel vector in a pre-clinical model of heart failure. In addition, we will analyze the prevalence of pre-existing neutralizing antibodies against our new cardiotropic vector in a heart failure patient population. In STAGE 2, we will carry out a phase 1, Open- Labeled, Dose-Escalation Trial of BNP111.sc-CMV.l1c by Intra-Coronary Infusion in Patients with Heart Failure followed by a A Phase 2, Randomized, Double-Blinded, Placebo-Controlled Dose Escalation Trial of Intra-Coronary Infusion of BNP111.sc-CMV.l1c in patients with heart failure. RELEVANCE (See instructions): Heart failure is a major cause of morbidity and mortality in the United States despite the novel therapies that are used to treat these patients. Gene therapy has emerged as a novel and viable strategy to target specific abnormalities in the failing heart. We have developed a cardiotropic Adeno-Associated Vector (AAV) that specifically targets the heart and escapes the inherent immunity in patients. This new cardiotropic vector combined with a novel well validated target offers a new strategy for the treatment of heart failure.