This year, we will newly diagnose one million Americans with heart failure at a cost of 30 billion dollars. Yet, only two thousand Americans will receive heart transplants and far fewer will receive mechanical ventricular assist devices. Emerging technologies include gene therapy which has the potential to save millions of lives. During the prior funding period we further developed an exciting new cardiac surgical technique, molecular cardiac surgery with recirculating delivery (MCARD), arguably the most efficient delivery system in the world for therapeutic genes in adult large animal myocardium. MCARD uses cardiopulmonary bypass with surgical isolation of the heart in vivo with delivery in situ. Use of MCARD to deliver AAV1 expressing SERCA2a results in efficient global LV transduction and significant improvement in EF, downregulation of TGF, inhibition of fibrosis and apoptosis as well as reversal of maladaptive remodeling. These promising preclinical results lead directly to the review by the FDA of a Pre-IND package, Molecular Cardiac Surgery Mediated Administration of AAV Encoding Sarcoplasmic Reticulum ATPase Gene in Patients with Heart Failure on 7-15-2014 in preparation for a First-In Man, First-In World clinical trial of gene therapy in patients with heart failure using cardiopulmonary bypass for vector delivery. We plan to build on these exciting results in the current proposal with three specific aims for molecular regenerative therapy in patients with ischemic cardiomyopathy - the cause of heart failure in 70% of Americans with this disease: 1) Delivery of AAV encoding miR-590 to induce proliferation of otherwise senescent adult cardiac myocytes; 2) Delivery of AAV encoding membrane bound stem cell factor (mSCF) to recruit and activate c-kit positive cardiac progenitor cells in the myocardium and 3) Development of a novel single-vector rapamycin-inducible promoter system to allow for long-term control of the expression of mSCF and miR-590 to optimize safety and efficacy and to allow for preemptive gene therapy in the setting of a future MI. This highly innovative proposal may change the paradigm of cardiac surgery from a palliative-only therapy to a molecular regenerative and preemptive cytoprotective intervention for selected patients.
The majority of heart failure cases in the United States occur after an acute myocardial infarction (MI) and gene therapy can correct the resultant molecular defects with the potential to help thousands of heart failure patients. In this innovative proposal we will use molecular cardiac surgery for highly efficient delivery of regenerative therapeutic genes to the heart. Allowing the heart to regenerate lost cardiac myocytes after MI in a clinically relevant large animal model is a new approach that should result in promising therapeutic options.
|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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