TRIP: Targeted Gene Therapy for the Treatment of Heart Failure

描述(由申请人提供)：虽然常规治疗的进展在降低心力衰竭死亡率方面取得了稳步和渐进的进展，但仍有迫切需要探索的问题 新的治疗方法。基因治疗是最近出现的一种治疗心力衰竭的新策略。我们团队最近完成了针对肌浆网钙ATPase泵(SERCA2a)的第一个人阶段和第二阶段试验，使用1型腺相关载体AAV1.SERCA2a。尽管AAV载体在这项试验中被证明是安全的，但它们被发现不是心脏特异性的，预先存在的中和抗体导致很大比例的患者被排除在外。我们已经开发了新型的AAV(也被称为生物纳米颗粒(BNP))的心脏亲和性嵌合体，它更具特异性地针对心脏，逃避患者的固有免疫。在该建议的第一阶段：1)我们开发并鉴定了一种新型BNP载体(BNP116)，它具有高度的向心性，同时去靶向肝脏、肺、肾脏和脑；2)我们已经证明它对先前的人类中和抗体具有更高的抵抗力(从而允许纳入更多患者)；3)我们已经证明携带具有固有活性的蛋白磷酸酶抑制物1(L1C)的BNP116在逆转猪心力衰竭模型的收缩功能障碍方面是有效的；4)我们已经完成了IND前的与FDA的会议，我们已经就最终毒理学研究的前进路径达成一致。在目前的第二阶段提案中，Deborah Ascheim博士将担任联合PI。她是西奈山国际健康结果和创新研究中心(INCHOIR)的临床研究主任和临床研究单位主任。她和她在INCHOIR的团队在多中心试验的设计、实施和分析方面拥有丰富的专业知识，包括使用复合终点、促进及时登记和减少特定地点的招募障碍。我们将进行BNP116 CMV.l1c的1期开放标记剂量递增试验，然后进行2期随机双盲安慰剂对照冠状动脉内注射BNP116 CMV.11c治疗心力衰竭患者的剂量递增试验。相关性(见说明)：充血性心力衰竭是美国发病率和死亡率的主要原因，迫切需要探索新的治疗方法。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，使心力衰竭进入了基于基因的治疗的范围。在这笔赠款中，我们在携程第一阶段的临床前工作的基础上，提出了使用新载体和治疗心力衰竭的新基因靶点进行基因治疗的第一阶段和第二阶段临床试验。

DESCRIPTION (provided by applicant): While progress in conventional treatments is making steady and incremental gains to reduce heart failure mortality, there is a critical need to explore new therapeutic approaches. Gene therapy has recently emerged as a novel strategy to treat heart failure. Our group has recently completed a First-in-Man Phase 1 and Phase 2 trials targeting the sarcoplasmic reticulum calcium ATPase pump (SERCA2a) using adenoassociated vector type 1 AAV1.SERCA2a. Even though AAV vectors have been proven to be safe in this trial, they have been found not to be specific for the heart and pre-existence neutralizing antibodies result in the exclusion of a large percentage of the patients. We have developed novel cardiotropic chimerics of AAV (which are also known as Bio Nano Particles (BNP) that more specifically target the heart and escape the inherent immunity in patients. In STAGE 1 of this proposal: 1) we have developed and characterized a novel BNP vector (BNP116) which has high cardiotropism while de-targeting the liver, lungs, kidneys and brain, 2) we have shown that it has higher resistance to antecedent human neutralizing antibodies (thereby allowing more patients to be included), 3) we have shown that BNP116 carrying the constitutively active form of protein phosphatase inhibitor 1 (l1c) is effective in reversing contractile dysfunction in a porcine model of HF, and 4) we have completed a pre-IND meeting with the FDA and we have agreed on a path forward for the final toxicology studies. In the current stage 2 proposal, Dr. Deborah Ascheim will be the Joint-PI. She is the Clinical Director of Research and Director of the Clinical Research Unit at the International Center for Health Outcomes & Innovation Research (InCHOIR) at Mount Sinai. She and her team at InCHOIR have significant expertise in the design, conduct and analysis of multi-center trials, including the use of composite endpoints, facilitating timely enrollment and reducing site-specific barriers to recruitment. We will carry ou a phase 1, Open-Labeled, Dose-Escalation Trial of BNP116.CMV.l1c followed by a Phase 2, Randomized, Double-Blinded Placebo-Controlled Dose Escalation Trial of Intra-Coronary Infusion of BNP116.CMV.l1c in Patients with Heart Failure. RELEVANCE (See instructions): Congestive heart failure is a major cause of morbidity and mortality in the US, and there is a critical need to explore new therapeutic approaches. Recent advances in understanding of the molecular basis of myocardial dysfunction, together with the evolution of increasingly efficient gene transfer technology, have placed heart failure within reach of gene-based therapy. In this grant, we build on our pre-clinical work in stage 1 of CTRIP to propose Phase 1 and Phase 2 clinical trials in gene therapy using novel vectors and a novel gene target for the treatment of heart failure.