We have defined a set of objectives that are initially scientific/regulatory in focus following on to clinically driven objectives. During the BAMI project our objectives are to:
Create a pre-clinical dossier, for a standardisation method for the preparation of bone marrow mononuclear cells for intra-coronary injection;
Standardise an intracoronary infusion method that allows for the safe and efficient delivery of cell therapy to the coronary artery;
Design a definite randomised control clinical trial that addresses whether the standardised mononuclear cell product confers an all-cause mortality benefit in patients with acute myocardial infarction who undergo primary angioplasty (25% reduction on top of standard therapy).
We will use the extensive experience of the clinical trialists that are members of the European Society of Cardiology and as a group form the most informed experts in the field of clinical cardiac regenerative medicine to perform the definitive clinical outcome trial that tests the results of the clinical trials to date. As part of this process we will also devise and define a method of standardisation and delivery of the cell product that is applicable across the EU. Regulatory issues will also be addressed to ensure that implementation of this therapy will be widely adopted. In order to ensure the rapid translation into man, the pre-existing clinical trial experience of the consortium will be used to design a protocol for standardisation of BMC preparation and injection. The design and execution of the clinical trial will take up the majority of the time/resource spent on this project.
State of the Art
In the setting of ST-elevation myocardial infarction (STEMI) the immediate reopening of acutely occluded coronary arteries via primary angioplasty (PPCI) is the treatment of choice to salvage the ischemic myocardium. However, the sudden re-initiation of blood flow, can lead to a local acute inflammatory response with further endothelial and myocardial damage. This phenomenon, described as 'reperfusion injury', may explain why, despite optimum myocardial reperfusion, the short-term mortality after AMI approaches 7% (7) and the incidence of heart failure approaches 15-20% (12, 13). Animal studies suggest that whilst 50% of the final infarct size is due to the ischaemic insult per se that the remaining 50% is due to reperfusion injury(14). Disappointingly, whilst several strategies have been shown to be effective in reducing ischaemia-reperfusion (I/R) injury in pre-clinical models, the majority of these approaches have not translated to the clinical setting with the notable exception of a recent small-scale study with cyclosporine (15). In this study, cyclosporine (a potent inhibitor of the mitochondrial transition pore) when injected intravenously before PPCI for AMI, significantly reduced infarct size as assessed by the creatine kinase profile. In addition, in a sub-group of patients it was demonstrated by CMR 5 days post-PPCI that cyclosporine treatment was associated with a reduced area of hyper-enhancement (infarcted tissue) as well as a decreased LV mass assessed at 6 months (16). One of the limiting factors of cyclosporine is its many side effects and the lack of regenerative potential, therefore providing a strong rationale for identification of alternative strategies that might also reduce infarct size but without a substantial side effect profile.
Several other potential pharmacological agents are under investigation however none of these offer the potential dual mode of action of reduction in ischemia reperfusion injury and cardiac regeneration that is offered by the cell therapy that we are proposing.