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正在稳步增加，以降低心力衰竭死亡率，但迫切需要探索 新的治疗方法。基因治疗是近年来出现的一种治疗心力衰竭的新策略。我们的研究小组最近完成了一项首次在人身上进行的1期和2期试验，该试验使用腺相关载体1型AAV1.SERCA2a靶向肌浆网钙ATP酶泵（SERCA2a）。尽管AAV载体在该试验中已被证明是安全的，但已发现它们对心脏不是特异性的，并且预先存在的中和抗体导致大部分患者被排除在外。我们已经开发了新的AAV（也称为生物纳米颗粒（BNP））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力。在本提案的第一阶段：1）我们已经开发并表征了一种新的BNP载体（BNP 116），其具有高的心肌向性，同时去靶向肝、肺、肾和脑，2）我们已经表明其对先前的人中和抗体具有更高的抗性，（从而允许包括更多的患者），3）我们已经表明，携带组成型活性形式的蛋白磷酸酶抑制剂1（l1c）的BNP 116，在HF猪模型中有效逆转收缩功能障碍，以及4）我们已经完成了与FDA的IND前会议，并且我们已经就最终毒理学研究的前进道路达成一致。在当前的第2阶段提案中，Deborah Ascheim博士将担任联合主要研究者。她是西奈山国际健康成果与创新研究中心（InCHOIR）的临床研究主任和临床研究部主任。她和她在InCHOIR的团队在多中心试验的设计，实施和分析方面具有重要的专业知识，包括使用复合终点，促进及时招募并减少招募的特定地点障碍。我们将进行BNP116.CMV.11c的1期、开放标签、剂量递增试验，随后进行心力衰竭患者冠状动脉内输注BNP116.CMV.11c的2期、随机、双盲安慰剂对照剂量递增试验。相关性（参见说明）：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。随着对心肌功能障碍分子基础的理解的不断深入，以及基因转移技术的不断发展，心力衰竭已进入基因治疗的范围。在这项资助中，我们在CTRIP第1阶段的临床前工作的基础上，提出了使用新型载体和新型基因靶点治疗心力衰竭的基因治疗的1期和2期临床试验。

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.