Idiopathic dilated cardiomyopathy (IDCM) is a leading cause of congestive heart failure, produces death and disability via heart failure and sudden cardiac death, and accounts for ~50% of heart transplants performed. As such this disorder is a lead candidate for cell-based therapy. The primary phenotype of dilated cardiomyopathy is an enlarged, remodeled ventricle with increases in end-diastolic and end-systolic volumes, reduced ejection fraction, and impaired contractile and diastolic function. Cell-based therapy holds great promise as a new approach to produce durable and sustainable improvements in dysfunctional hearts and to cause reverse remodeling. If these effects can be clinically established and optimized, there is enormous potential for improving clinical outcomes for the many patients suffering from dilated cardiomyopathy. Our group has extensive experience with catheter delivery of bone-marrow derived mesenchymal stem cells in patients with ischemic cardiomyopathy and is now poised to test this exciting clinical hypothesis in patients with non-ischemic cardiomyopathy. There is substantial scientific and public interest for cardiac regenerative cell therapy strategies, based on pre-clinical, translational, and early clinical studies. This trial is currently approved by the FDA under investigator initiated IND number BB-14419 (PI: Hare), and is therefore ready to be initiated.
The specific aims of this proposal are: 1. To establish the safety and efficacy of bone marrow derived mesenchymal stem cell (MSC) therapy for patients with idiopathic dilated cardiomyopathy. We will perform a randomized comparison of autologous and allogeneic MSC therapy employing percutaneous delivery with a transendocardial catheter delivery system. 2. To compare two different bone marrow preparations - allogeneic vs. autologous bone marrow derived mesenchymal stem cells (MSCs) - for safety and efficacy in patients with non-ischemic cardiomyopathy. The mechanism of action at a phenotypic level will be assessed using cardiac magnetic resonance imaging (MRI) to measure MI size, regional and global LV function, tissue fibrosis, and tissue perfusion. A post-hoc analysis will be performed to test the hypothesis that in vitro assessments of cell morphology, cell surface markers, and cell colony growth potential may predict the ability of an individual patient's cells to improve the cardiac measures. 3. To assess cellular mechanisms of action of MSC therapy by measuring the capacity for endogenous cardiac stem cell proliferation and differentiation. Endomyocardial biopsies will be obtained from the patients enrolled in this trial and tested for their capacity to yield endogenous cardiac stem cells.

Public Health Relevance

This clinical study will address a significant clinical need, namely the investigation of new and promising therapies for heart failure, one of the leading causes of cardiovascular death and disability. The proposed studies will elucidate new mechanisms of repair and regeneration of heart tissue.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01HL110737-04
Application #
8680353
Study Section
Myocardial Ischemia and Metabolism Study Section (MIM)
Program Officer
Buxton, Denis B
Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Miami School of Medicine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Coral Gables
State
FL
Country
United States
Zip Code
33146
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Hatzistergos, Konstantinos E; Hare, Joshua M (2016) Murine Models Demonstrate Distinct Vasculogenic and Cardiomyogenic cKit+ Lineages in the Heart. Circ Res 118:382-7
Florea, Victoria; Balkan, Wayne; Schulman, Ivonne Hernandez et al. (2016) Cell Therapy Augments Myocardial Perfusion and Improves Quality of Life in Patients With Refractory Angina. Circ Res 118:911-5
Hatzistergos, Konstantinos E; Saur, Dieter; Seidler, Barbara et al. (2016) Stimulatory Effects of Mesenchymal Stem Cells on cKit+ Cardiac Stem Cells Are Mediated by SDF1/CXCR4 and SCF/cKit Signaling Pathways. Circ Res 119:921-30
Hare, Joshua M; DiFede, Darcy L; Castellanos, Angela M et al. (2016) Randomized Comparison of Allogeneic Vs. Autologous Mesenchymal Stem Cells for Non-lschemic Dilated Cardiomyopathy: POSEIDON-DCM Trial. J Am Coll Cardiol :
Golpanian, Samuel; Schulman, Ivonne H; Ebert, Ray F et al. (2016) Concise Review: Review and Perspective of Cell Dosage and Routes of Administration From Preclinical and Clinical Studies of Stem Cell Therapy for Heart Disease. Stem Cells Transl Med 5:186-91
Goldstein, Bradley J; Goss, Garrett M; Hatzistergos, Konstantinos E et al. (2015) Adult c-Kit(+) progenitor cells are necessary for maintenance and regeneration of olfactory neurons. J Comp Neurol 523:15-31
Tamariz, Leonardo; Hare, Joshua M (2015) Xanthine oxidase inhibitors in heart failure: where do we go from here? Circulation 131:1741-4
Grabner, Alexander; Amaral, Ansel P; Schramm, Karla et al. (2015) Activation of Cardiac Fibroblast Growth Factor Receptor 4 Causes Left Ventricular Hypertrophy. Cell Metab 22:1020-32
Ding, Wen; Li, Jihe; Singh, Jayanti et al. (2015) miR-30e targets IGF2-regulated osteogenesis in bone marrow-derived mesenchymal stem cells, aortic smooth muscle cells, and ApoE-/- mice. Cardiovasc Res 106:131-42

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