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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Specialized Center (P50)
Project #
Application #
Study Section
Special Emphasis Panel (ZHL1-CSR-H (F1))
Program Officer
Shah, Monica R
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Icahn School of Medicine at Mount Sinai
Internal Medicine/Medicine
Schools of Medicine
New York
United States
Zip Code
Fish, Kenneth M; Ishikawa, Kiyotake; Hajjar, Roger J (2017) Stem cell therapy for acute myocardial infarction: on the horizon or still a dream? Coron Artery Dis :
Guénantin, Anne-Claire; Briand, Nolwenn; Capel, Emilie et al. (2017) Functional Human Beige Adipocytes From Induced Pluripotent Stem Cells. Diabetes 66:1470-1478
Watanabe, Shin; Fish, Kenneth; Bonnet, Guillaume et al. (2017) Echocardiographic and hemodynamic assessment for predicting early clinical events in severe acute mitral regurgitation. Int J Cardiovasc Imaging :
Sultana, Nishat; Magadum, Ajit; Hadas, Yoav et al. (2017) Optimizing Cardiac Delivery of Modified mRNA. Mol Ther 25:1306-1315
Kranias, Evangelia G; Hajjar, Roger J (2017) The Phospholamban Journey 4 Decades After Setting Out for Ithaka. Circ Res 120:781-783
Sahoo, Susmita; Mathiyalagan, Prabhu; Hajjar, Roger J (2017) Pericardial Fluid Exosomes: A New Material to Treat Cardiovascular Disease. Mol Ther 25:568-569
Hajjar, Roger J; Ishikawa, Kiyotake (2017) Introducing Genes to the Heart: All About Delivery. Circ Res 120:33-35
Lee, Ahyoung; Oh, Jae Gyun; Gorski, Przemek A et al. (2016) Post-translational Modifications in Heart Failure: Small Changes, Big Impact. Heart Lung Circ 25:319-24
Jang, Seung Pil; Oh, Jae Gyun; Kang, Dong Hoon et al. (2016) A Decoy Peptide Targeted to Protein Phosphatase 1 Attenuates Degradation of SERCA2a in Vascular Smooth Muscle Cells. PLoS One 11:e0165569
Hulot, Jean-Sebastien; Ishikawa, Kiyotake; Hajjar, Roger J (2016) Gene therapy for the treatment of heart failure: promise postponed. Eur Heart J 37:1651-8

Showing the most recent 10 out of 49 publications