TRIP: Targeted Gene Therapy for the Treatment of Heart Failure

TRIP：治疗心力衰竭的靶向基因疗法

• 批准号: 8251322
• 负责人: Deborah Davis Ascheim
• 金额: $ 216.84万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8251322
• 关键词: Biological; Brain; Cardiac; Cardiomyopathies; Cardiopulmonary; Case Report Form; Clinical; Clinical Research; Clinical Trials Data Monitoring Committees; Congestive Heart Failure; Constitution; Contracts; Coronary; Coronary artery; Cytomegalovirus; Development; Disease; Dose; Double-Blind Method; Echocardiography; Elements; Enrollment; Event; Evolution; Exclusion; Exercise; Experimental Models; FDA approved; Family suidae; Functional disorder; Future; Gene Delivery; Gene Targeting; Gene Transfer; Goals; Grant; Health; Heart; Heart failure; Human; Immunity; Individual; Informed Consent; Infusion procedures; Inherited; Institutional Review Boards; Instruction; International; Joints; Kidney; Liver; Lung; Manuals; Modeling; Molecular; Morbidity - disease rate; Myocardial dysfunction; NT-proBNP; Outcome; Patients; Phase; Phase II Clinical Trials; Placebo Control; Policies; Proteins; Protocols documentation; Pump; Randomized; Research; Research Infrastructure; Resistance; SERCA2a; Safety; Serotyping; Site; Staging; Structure; Symptoms; System; Technology; Testing; Toxicology; Transgenes; United States; Work; adeno-associated viral vector; adjudication; artery infusion; base; conventional therapy; design; double-blind placebo controlled trial; electronic data; functional status; gene therapy; inhibitor/antagonist; innovation; international center; man; medical schools; meetings; mortality; nanoparticle; neutralizing antibody; novel; novel strategies; novel therapeutic intervention; open label; operation; phase 1 study; phase 2 study; pre-clinical; protein phosphatase inhibitor-1; sarcoplasmic reticulum calcium ATPase; vector

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.

描述（由申请人提供）：虽然传统治疗方法在降低心力衰竭死亡率方面取得了稳定和渐进的进展，但仍迫切需要探索 新的治疗方法。基因疗法最近成为治疗心力衰竭的一种新策略。我们的小组最近使用腺相关载体 1 型 AAV1.SERCA2a 完成了针对肌浆网钙 ATP 酶泵 (SERCA2a) 的首次人体 1 期和 2 期试验。尽管 AAV 载体在该试验中已被证明是安全的，但人们发现它们对心脏不具有特异性，并且预先存在的中和抗体导致很大一部分患者被排除在外。我们开发了新型 AAV 的心肌嵌合体（也称为生物纳米颗粒 (BNP)，更专门针对心脏并逃避患者固有的免疫力。在该提案的第一阶段：1) 我们开发并表征了一种新型 BNP 载体 (BNP116)，它具有高心肌活性，同时去靶向肝脏、肺、肾脏和大脑，2) 我们已经证明它具有 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，携带蛋白磷酸酶抑制剂 1 (l1c) 组成型活性形式的 BNP116 可有效逆转心力衰竭猪模型中的收缩功能障碍，4) 我们已经与 FDA 完成了 IND 前会议，并就最终研究的前进方向达成了一致 毒理学研究。在当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成果与创新研究中心 (InCHOIR) 的临床研究总监和临床研究部主任。她和她在 InCHOIR 的团队在多中心试验的设计、实施和分析方面拥有丰富的专业知识，包括使用复合终点、促进及时入组和减少特定地点的招募障碍。我们将开展 BNP116.CMV.11c 的 1 期、开放标签、剂量递增试验，随后在心力衰竭患者中进行 2 期、随机、双盲、安慰剂对照剂量递增试验，对 BNP116.CMV.11c 进行冠状动脉内输注。相关性（参见说明）：充血性心力衰竭是美国发病和死亡的主要原因，迫切需要探索新的治疗方法。对心肌功能障碍的分子基础的了解的最新进展，加上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。在这笔资助中，我们以 CTRIP 第一阶段的临床前工作为基础，提出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第一阶段和第二阶段临床试验。