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TRIP: Targeted Gene Therapy for the Treatment of Heart Failure

TRIP：治疗心力衰竭的靶向基因疗法

基本信息

批准号：
8657103
负责人：
Deborah Davis Ascheim
金额：
$ 208.23万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-05-01 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8657103
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

项目摘要

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，但仍有迫切需要进行探索