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

C-TRIP：治疗心力衰竭的靶向基因治疗（P20）

• 批准号: 8010649
• 负责人: Roger J. Hajjar
• 金额: $ 84.75万
• 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: 2010-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8010649
• 关键词: Accounting; Animal Model; Biological; Ca(2+)-Transporting ATPase; Cardiac; Clinical; Congestive Heart Failure; Coronary; Cytomegalovirus; Defect; Dose; Double-Blind Method; Evolution; Experimental Models; Fibrosis; Gene Delivery; Gene Transduction Agent; Gene Transfer; Heart; Heart failure; Human; Immunity; Individual; Infusion procedures; Instruction; Metabolism; Molecular; Morbidity - disease rate; Myocardial dysfunction; Patients; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Placebo Control; Pre-Clinical Model; Prevalence; Progressive Disease; Randomized; Relaxation; SERCA2a; Safety; Sarcoplasmic Reticulum; Serotyping; Signal Transduction; Technology; United States; Ventricular Dysfunction; base; gene therapy; improved functioning; innovation; man; mortality; nanoparticle; neutralizing antibody; novel; open label; patient population; phospholamban; protein phosphatase inhibitor-1; treatment strategy; uptake; vector

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.

描述（由申请人提供）： 尽管治疗方法不断增多，充血性心力衰竭（HF）仍然是一种进行性疾病。因此，迫切需要创新而非增量疗法来逆转心室功能障碍的进程。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，使心力衰竭成为基于基因的治疗的范围。人类和实验性心力衰竭的关键细胞改变之一是肌浆网 (SR) 功能缺陷，这是导致衰竭心肌细胞中观察到的异常细胞内 Ca2+ 处理的原因1-4 在人类和动物模型的衰竭心脏中，已发现舒张期间 SR Ca2+ 摄取不足，并且与 SR 活性降低有关 Ca2+-ATPase (SERCA2a)，这至少部分归因于受磷蛋白 (PLN) 抑制的增强。在许多心力衰竭实验模型中，恢复 SERCA2a 水平或减少 PLN 抑制已被证明可以改善功能、代谢和/或生存。在过去的十年中，我们启动并最近完成了一项首次人体 1 期临床试验，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。 AAV 基因治疗的安全性以及从该 1 期试验中获得的积极生物信号导致在 NYHA III/IV 级患者中启动 AAV1.SERCA2a 2 期试验6。最近，我们发现，通过在衰竭心脏内组成型激活蛋白磷酸酶 1 (l-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大来逆转不良重塑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，但它们用于基因传递具有以下局限性：1) 它们对心脏不具有特异性，2) 任何个体血清型的先前中和抗体占这些患者的 40%，需要将其排除在临床试验之外14-17。因此，我们开发了一种 AAV 的心肌嵌合体，它更具体地针对心脏并逃避患者固有的免疫力。因此，我们建议利用这些新型嵌合载体（也称为生物纳米颗粒 (BNP)）在心力衰竭实验模型中直接靶向 I-114-17。在该提案的第一阶段，我们将在心力衰竭的临床前模型中使用这种新型载体来验证目标。此外，我们将分析心力衰竭患者群体中预先存在的针对我们新的心肌载体的中和抗体的流行情况。在第 2 阶段，我们将在心力衰竭患者中进行 BNP111.sc-CMV.l1c​​ 冠状动脉内输注的 1 期、开放标签、剂量递增试验，然后在心力衰竭患者中进行 BNP111.sc-CMV.l1c​​ 冠状动脉内输注的 A 期 2 期、随机、双盲、安慰剂对照剂量递增试验。 相关性（参见说明）：尽管有新的疗法用于治疗这些患者，但心力衰竭是美国发病和死亡的主要原因。基因治疗已成为一种针对衰竭心脏的特定异常的新颖且可行的策略。我们开发了一种心肌腺相关载体（AAV），专门针对心脏并逃避患者固有的免疫力。这种新的心肌载体与经过充分验证的新型靶标相结合，为心力衰竭的治疗提供了新的策略。