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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-CVS-C (02))
Program Officer
Skarlatos, Sonia
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Pennsylvania
Schools of Medicine
United States
Zip Code
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
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:
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
Katz, Michael G; Brandon-Warner, Elizabeth; Fargnoli, Anthony S et al. (2016) Mitigation of myocardial fibrosis by molecular cardiac surgery-mediated gene overexpression. J Thorac Cardiovasc Surg 151:1191-200.e3
Katz, Michael G; Fargnoli, Anthony S; Kendle, Andrew P et al. (2016) The role of microRNAs in cardiac development and regenerative capacity. Am J Physiol Heart Circ Physiol 310:H528-41
Fargnoli, A S; Katz, M G; Williams, R D et al. (2016) Liquid jet delivery method featuring S100A1 gene therapy in the rodent model following acute myocardial infarction. Gene Ther 23:151-7
Williams, R D; Katz, M G; Fargnoli, A S et al. (2016) Bochdalek Congenital Diaphragmatic Hernia in an Adult Sheep. Anat Histol Embryol 45:246-8
Katz, Michael G; Fargnoli, Anthony S; Kendle, Andrew P et al. (2015) Characterizing preclinical model of ischemic heart failure: difference between LAD and LCx infarctions. Am J Physiol Heart Circ Physiol 308:H364
Katz, Michael G; Fargnoli, Anthony S; Williams, Richard D et al. (2014) The road ahead: working towards effective clinical translation of myocardial gene therapies. Ther Deliv 5:39-51
Fargnoli, A S; Katz, M G; Williams, R D et al. (2014) A needleless liquid jet injection delivery method for cardiac gene therapy: a comparative evaluation versus standard routes of delivery reveals enhanced therapeutic retention and cardiac specific gene expression. J Cardiovasc Transl Res 7:756-67

Showing the most recent 10 out of 27 publications