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

描述(由申请人提供)： 尽管治疗方法层出不穷，充血性心力衰竭(HF)仍是一种进行性疾病。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。在了解心肌功能障碍的分子基础方面的最新进展，以及日益有效的基因转移技术的发展，使心力衰竭进入了基于基因的治疗的范围。肌浆网(SR)功能的缺陷是人和实验性心衰的关键细胞改变之一，这是衰竭心肌细胞内钙处理异常的原因。在人和动物模型的衰竭心脏中，已发现肌浆网在松弛过程中摄取肌浆网钙的缺陷，并与肌浆网钙-ATPase(SERCA2a)活性降低有关，这至少部分是由于磷蛋白(PLN)抑制作用增强。在一些心力衰竭的实验模型中，恢复SERCA2a水平或减少PLN抑制已被证明可以改善功能、代谢和/或存活率。在过去的十年里，我们已经启动并最近完成了使用携带SERCA 2a5的腺相关1型(AAV)载体进行心力衰竭基因治疗的首个人一期临床试验。AAV基因治疗的安全性以及从这项1期试验中获得的阳性生物信号已导致AAV1的SERCA2a在NYHA III/IV级患者6中启动了2期试验。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抑制物1(L-1)，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脏肥厚7-13，逆转不利的重构。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，但它们用于基因传递有以下限制：1)它们不是心脏特异性的；2)任何单个血清型的先前中和抗体占这些患者的40%，需要从临床试验14-17中排除。因此，我们开发了一种AAV的向心性嵌合体，它更具体地针对心脏，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，也被称为生物纳米颗粒(BNP)，在心力衰竭的实验模型14-17中直接靶向I-1。在这项提议的第一阶段，我们将在心力衰竭的临床前模型中使用这种新的载体来验证目标。此外，我们还将分析在心力衰竭患者群体中针对我们新的嗜心载体的预先存在的中和抗体的流行率。在第二阶段，我们将进行BNP111.sc-CMV.l1c心力衰竭患者冠状动脉内注射BNP111.sc-CMV.l1c的第1阶段开放标签剂量递增试验，随后将进行A阶段2随机、双盲、安慰剂对照的心力衰竭患者冠状动脉内输注BNP111.sc-CMV.l1c的剂量递增试验。相关性(见说明书)：心力衰竭是美国发病率和死亡率的主要原因，尽管有新的治疗方法用于治疗这些患者。基因治疗已经成为针对衰竭心脏中特定异常的一种新颖而可行的策略。我们已经开发出一种嗜心性腺相关载体(AAV)，它专门针对心脏，并逃避患者的固有免疫。这种新的心力性载体与一个新的有效靶点相结合，为治疗心力衰竭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.