This year, one million Americans will die of heart failure at a cost of 25 billion dollars. Yet, only two thousand Americans will receive heart transplants and even fewer will receive mechanical ventricular assist devices. Gene therapy is an important emerging technology with the potential to save thousands of lives. Correction of the heart failure phenotype has been convincingly demonstrated in transgenic mice, rabbit and rodent models of heart failure using the beta adreno-receptor kinase C-terminus (BARKct)) as a therapeutic transgene. Prior to our work, none of the delivery techniques utilized to date has been clinically translatable and had high global myocyte transduction efficiency. These observations galvanize our central hypothesis: the rate-limiter in the quest for clinically relevant heart failure gene therapy is the successful achievement of global vector-mediated gene delivery to a significant percentage of cardiac myocytes in situ in a translational animal model. Here we present our success in developing an exciting new cardiac surgical technique that efficiently delivers marker transgenes to adult large animal cardiac myocytes in situ using cardiopulmonary bypass with surgical isolation of the heart in vivo and in situ, coupled with multiple-pass recirculation of recombinant vector in the coronary circulation. This procedure allows for control of multiple variables to optimize myocyte gene delivery efficiency while minimizing the probability of collateral gene expression. We also present exciting new data using both constitutive and cardiac-specific promoters demonstrating highly efficient cardiac myocyte transduction with AAV6 in a heart failure model and preliminary data with AAV9 in the murine heart. In the first year we further optimize the global delivery technique using these novel AAV serotypes in the normal sheep heart. In years two through four we use the improved gene delivery methodology to administer novel AAV constructs encoding BARKct to the heart in an ovine model that closely mimics human ischemic cardiomyopathy. We use 3D MRI and invasive hemodynamic studies to assess load-independent and load-dependent indices of cardiac mechanics and myocardial energetics. The effects of gene expression on remodeling, adrenergic cycling, heart failure markers and survival will be assessed for up to one year. Successful completion of this study may lead to alternatives to heart transplantation and permanent mechanical assist devices in the treatment of end stage heart failure. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL083078-02
Application #
7420983
Study Section
Special Emphasis Panel (ZRG1-CVS-C (02))
Program Officer
Skarlatos, Sonia
Project Start
2007-06-01
Project End
2011-05-31
Budget Start
2008-06-01
Budget End
2009-05-31
Support Year
2
Fiscal Year
2008
Total Cost
$727,681
Indirect Cost
Name
University of Pennsylvania
Department
Surgery
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Katz, Michael G; Fargnoli, Anthony S; Yarnall, Charles et al. (2018) Technique of Complete Heart Isolation with Continuous Cardiac Perfusion During Cardiopulmonary Bypass: New Opportunities for Gene Therapy. J Extra Corpor Technol 50:193-198
Katz, Michael G; Fargnoli, Anthony S; Hajjar, Roger J et al. (2018) Pulmonary hypertension arising from left heart disease causes intrapulmonary venous arterialization in rats. J Thorac Cardiovasc Surg 155:281-282
Katz, Michael G; Fargnoli, Anthony S; Hajjar, Roger J et al. (2017) In Situ Heart Isolation Featuring Closed Loop Recirculation: The Gold Standard for Optimum Cardiac Gene Transfer? Adv Tech Biol Med 5:
Hadas, Yoav; Katz, Michael G; Bridges, Charles R et al. (2017) Modified mRNA as a therapeutic tool to induce cardiac regeneration in ischemic heart disease. Wiley Interdiscip Rev Syst Biol Med 9:
Maslov, M; Foianini, S; Lovich, M (2017) Response to the letter to the editor: delivery of drugs, growth factors, genes and stem cells via intrapericardial, epicardial and intramyocardial routes for sustained local targeted therapy of myocardial disease. Expert Opin Drug Deliv 14:911
Katz, Michael G; Fargnoli, Anthony S; Weber, Thomas et al. (2017) Use of Adeno-Associated Virus Vector for Cardiac Gene Delivery in Large-Animal Surgical Models of Heart Failure. Hum Gene Ther Clin Dev 28:157-164
Katz, Michael G; Fargnoli, Anthony S; Kendle, Andrew P et al. (2017) Molecular Cardiac Surgery with Recirculating Delivery (MCARD): Procedure and Vector Transfer. Methods Mol Biol 1521:271-289
Katz, M G; Fargnoli, A S; Hajjar, R J et al. (2017) Delivery of drugs, growth factors, genes and stem cells via intrapericardial, epicardial and intramyocardial routes for sustained local targeted therapy of myocardial disease. Expert Opin Drug Deliv 14:909-910
Ylä-Herttuala, Seppo; Bridges, Charles; Katz, Michael G et al. (2017) Angiogenic gene therapy in cardiovascular diseases: dream or vision? Eur Heart J 38:1365-1371
Katz, Michael G; Fargnoli, Anthony S; Kendle, Andrew P et al. (2016) Gene Therapy in Cardiac Surgery: Clinical Trials, Challenges, and Perspectives. Ann Thorac Surg 101:2407-16

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