Despite the proliferation of therapies, congestive heart failure (HF) remains a progressive disease. The impact of angiotensin converting enzyme inhibitors (ACEI) and b-blockers has translated into more sustained benefit, but many patients become intolerant to b-blockers in late stage disease. There is therefore a desperate need for innovative rather than incremental therapies to reverse the course of ventricular dysfunction. HF induced by genetic or specific conditions, such as coronary artery disease, hypertension, diabetes, infection, or inflammation results in a heterogeneous myocardium consisting of a mixture of replacement fibrosis, dysfunctional and normal myocytes. The normal myocytes that remain are under continuous stress from hormonal and physical stimuli that can induce apoptosis and cell death or render them dysfunctional. Thus, their preservation is the target of current therapies with neurohormonal blockade. Recent advances in understanding the molecular basis of myocardial dysfunction, together with the evolution of increasingly efficient gene transfer technology, have placed some cardiovascular diseases within reach of gene-based therapies. One of the key abnormalities in both human and experimental HF is a defect in sarcoplasmic reticulum (SR) function, which is responsible for abnormal intracellular Ca2+ handling. Deficient SR Ca2+ uptake during relaxation has been identified in failing hearts from both humans and animal models and has been associated with a decrease in the activity of the SR Ca2+-ATPase (SERCA2a), which is at least partially due to enhanced phospholamban (PLN) inhibition. Restoring SERCA2a levels or reducing PLN inhibition has been shown to improve function, metabolism and/or survival in rodent models of heart failure. More recently, we have shown that by constitutively activating the inhibitor of protein phosphatase 1 (I-1) within the failing heart, there is improvement of SR Ca2+-handling, contractility and, most importantly, reversal of adverse remodeling by directly decreasing fibrosis and cardiac hypertrophy. We therefore propose to take advantage of novel vectors, which we have developed for cardiac specific gene transfer to directly target cardiac I-1. These novel cardiotropic vectors, which are also known as Bio Nano Particles (BNP), are based on recombinant adeno-associated virus technology which exhibit very high cardiac tropisms. Combining these novel cardiotropic vectors with an important intracellular target may provide a novel paradigm for the treatment of heart failure.

Public Health Relevance

Over the last ten years, we have undertaken a program of targeting important calcium cycling proteins which has led to the first in man clinical trial of gene therapy for heart failure using adeno-associated type 1 (AAV) vector carrying the cardiac Sarcoplasmic Reticulum Calcium ATPase pump (SERCA2a). The use of AAV serotypes for gene delivery is limited in that they are not specific for the heart. We have developed a cardiotropic chimeric of AAV that specifically targets the heart and escapes the inherent immunity in patients and it is this new cardiotropic vector when combined with a novel well validated target that will offer a new paradigm for the treatment of heart failure.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL088434-03
Application #
8197466
Study Section
Special Emphasis Panel (ZRG1-CVRS-K (02))
Program Officer
Buxton, Denis B
Project Start
2010-03-01
Project End
2013-11-30
Budget Start
2011-12-01
Budget End
2012-11-30
Support Year
3
Fiscal Year
2012
Total Cost
$419,513
Indirect Cost
$172,013
Name
Icahn School of Medicine at Mount Sinai
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Watanabe, Shin; Ishikawa, Kiyotake; Fish, Kenneth et al. (2017) Protein Phosphatase Inhibitor-1 Gene Therapy in a Swine Model of Nonischemic Heart Failure. J Am Coll Cardiol 70:1744-1756
Chen, Jiqiu; Hammoudi, Nadjib; Benard, Ludovic et al. (2016) The Probability of Inconstancy in Assessment of Cardiac Function Post-Myocardial Infarction in Mice. Cardiovasc Pharm Open Access 5:
Kho, Changwon; Lee, Ahyoung; Jeong, Dongtak et al. (2015) Small-molecule activation of SERCA2a SUMOylation for the treatment of heart failure. Nat Commun 6:7229
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
Giannarelli, Chiara; Alique, Matilde; Rodriguez, David T et al. (2014) Alternatively spliced tissue factor promotes plaque angiogenesis through the activation of hypoxia-inducible factor-1? and vascular endothelial growth factor signaling. Circulation 130:1274-86
Ishikawa, Kiyotake; Aguero, Jaume; Tilemann, Lisa et al. (2014) Characterizing preclinical models of ischemic heart failure: differences between LAD and LCx infarctions. Am J Physiol Heart Circ Physiol 307:H1478-86
Lee, Ahyoung; Jeong, Dongtak; Mitsuyama, Shinichi et al. (2014) The role of SUMO-1 in cardiac oxidative stress and hypertrophy. Antioxid Redox Signal 21:1986-2001
Chaanine, Antoine H; Nonnenmacher, Mathieu; Kohlbrenner, Erik 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 21:379-386
Pereda, Daniel; García-Alvarez, Ana; Sánchez-Quintana, Damián et al. (2014) Swine model of chronic postcapillary pulmonary hypertension with right ventricular remodeling: long-term characterization by cardiac catheterization, magnetic resonance, and pathology. J Cardiovasc Transl Res 7:494-506
Hajjar, Roger J; Lyon, Alexander R (2014) Gene therapy for the treatment of catecholaminergic polymorphic ventricular tachycardia. Circulation 129:2633-5

Showing the most recent 10 out of 65 publications