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.
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.
|Ishikawa, Kiyotake; Fish, Kenneth; Aguero, Jaume et al. (2015) Stem cell factor gene transfer improves cardiac function after myocardial infarction in swine. Circ Heart Fail 8:167-74|
|Hajjar, Roger J; Hulot, Jean-Sebastien (2014) Modeling CVD in human pluripotent cells by genome editing. J Am Coll Cardiol 64:460-2|
|Yerevanian, Armen; Yerevanian, Alexan; Hajjar, Roger J (2014) Progress in gene therapy for heart failure. J Cardiovasc Pharmacol 63:95-106|
|Lipskaia, Larissa; Keuylian, Zela; Blirando, Karl et al. (2014) Expression of sarco (endo) plasmic reticulum calcium ATPase (SERCA) system in normal mouse cardiovascular tissues, heart failure and atherosclerosis. Biochim Biophys Acta 1843:2705-18|
|Karakikes, Ioannis; Senyei, Grant D; Hansen, Jens et al. (2014) Small molecule-mediated directed differentiation of human embryonic stem cells toward ventricular cardiomyocytes. Stem Cells Transl Med 3:18-31|
|Wahlquist, Christine; Jeong, Dongtak; Rojas-Muñoz, Agustin et al. (2014) Inhibition of miR-25 improves cardiac contractility in the failing heart. Nature 508:531-5|
|Chaanine, A H; Nonnenmacher, M; Kohlbrenner, E et al. (2014) Effect of bortezomib on the efficacy of AAV9.SERCA2a treatment to preserve cardiac function in a rat pressure-overload model of heart failure. Gene Ther 21:379-86|
|Hajjar, Roger J; Lyon, Alexander R (2014) Gene therapy for the treatment of catecholaminergic polymorphic ventricular tachycardia. Circulation 129:2633-5|
|Naim, Charbel; Yerevanian, Armen; Hajjar, Roger J (2013) Gene therapy for heart failure: where do we stand? Curr Cardiol Rep 15:333|
|Hajjar, Roger J (2013) Potential of gene therapy as a treatment for heart failure. J Clin Invest 123:53-61|
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