This program will have a major impact in the field of cell-based therapy for the leading cause of death and disability in patients with type 2 diabetes (DM), namely cardiovascular disease (CVD). Endothelial dysfunction underlies the high rates of CVD associated with long-term DM. We will conduct a phase I/II, randomized double-blind study testing the efficacy and safety of allogeneic bone marrow derived mesenchymal stem cells (MSCs) vs. placebo in patients with type 2 DM, endothelial dysfunction and ischemic heart disease. This trial is built on a solid foundation of 6 phase I/II trials conducted by our group that evaluated the safety and efficacy of autologous and allogeneic MSCs in patients with ischemic and non-ischemic CVD. MSCs improve endothelial progenitor cell (EPC) function and systemic endothelial function (measured by brachial artery flow-mediated dilation, FMD%) in patients with ischemic as well as non-ischemic cardiomyopathy, including non-DM and DM patients, suggesting that we now have a means to target a primary cause of the CV manifestations of DM. Moreover, the effect on EPCs and FMD% was sustained (3 months after MSC administration) and evident in patients receiving allogeneic, but not autologous, MSCs. Accordingly, this phase I/II study is timely, warranted, and could have a major health impact by addressing an unmet need in a large population of patients at risk for myocardial infarction, heart failure, sudden cardiac death, and recurrent hospitalizations. This study will break new ground in the field in several respects. It will establish the efficacy of allogeneic MSC intravenous (IV) delivery on systemic endothelial function (assessed by EPC function and FMD%) as well as coronary artery endothelialization and vessel healing post-percutaneous coronary intervention (PCI). Although safety has already been established by previous phase I/II trials of intravenous MSC delivery, additional safety data will be determined from this DM population with ischemic heart disease. The proposed study will accomplish 3 aims: 1) Test the hypothesis that IV delivery of allogeneic MSCs stimulates EPC function and circulating angiogenic growth factors and improves FMD% in type 2 DM patients; 2) Test the hypothesis that IV delivery of MSCs improves 3 month post-PCI endothelialization and vessel healing in DM patients (assessed using optical coherence tomography); 3) Test the hypothesis that allogeneic MSCs promote endothelial repair through rescue of bone marrow progenitors in DM patients with ischemic heart disease. Bone marrow biopsies will be obtained from DM patients at 3 months after MSC or placebo infusion for a detailed molecular and functional assessment of the effect of IV allogeneic MSCs on bone marrow autologous MSC and EPCs. Together, the studies proposed in this application will advance our understanding of this promising cellular-based therapy and address a major unmet need in DM patients with CVD. This clinical trial program is highly significant as cellular therapy offers the potential to restore endothelial function in this population at high risk for CVD morbidity and mortality.

Public Health Relevance

Myocardial infarction occurs when blood supply to the heart is inadequate, due to the impaired health and function of the blood vessel wall, and this represents the leading cause of death worldwide. Patients with type 2 diabetes are at even higher risk of death and disability from myocardial infarction than non-diabetics. In this proposal, we will explore cellular and molecular mechanisms through which the blood vessel wall can be protected against or healed after injury. Our findings will have implications for developing new therapeutic strategies for myocardial infarction and other related cardiovascular diseases.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL134558-02
Application #
9339723
Study Section
Clinical and Integrative Cardiovascular Sciences Study Section (CICS)
Program Officer
Buxton, Denis B
Project Start
2016-09-01
Project End
2021-06-30
Budget Start
2017-07-01
Budget End
2018-06-30
Support Year
2
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of Miami School of Medicine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
052780918
City
Coral Gables
State
FL
Country
United States
Zip Code
33146
Eschenhagen, Thomas; Bolli, Roberto; Braun, Thomas et al. (2017) Cardiomyocyte Regeneration: A Consensus Statement. Circulation 136:680-686