Evaluating the efficacy of a miR-10 therapy after myocardial infarction

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Myocardial loss due to myocardial infarction (MI) triggered by atherothrombotic occlusion of coronary vessels is the major risk factor for post-ischemic heart failure and sudden cardiac death world wide. While major advances have been made in treating acute myocardial infarction including catheter based interventions and novel adjunctive medical treatments, long-term mortality and hospitalization rates increased due to post-ischemic heart failure. Todays potent therapeutic approaches to improve the outcome after MI aim at inhibiting platelet and neuroendocrine activation. Novel molecular therapy options target at increasing coronary blood flow by inducing and enhancing new capillary and collateral arterial vessel formation. While several gene therapy approaches introducing classical single proangiogenic growth factors failed to demonstrate effectiveness in clinical trials, recent progress in miRNA based gene therapies hold great promise and proved potency in large animal trials. In previous work by us and others, miR-10 was established as a potent positive modulator of angiogenesis in zebrafish, mouse and human endothelial cells. Noticeably, miR-10s pro-angiogenic function is particularly mediated through paracrine mechanisms. Besides it pro-angiogenic function, it was shown by several others that forced expression of miR-10 in a cell actively blocked apoptosis and that miR-10, also in a paracrine fashion, is able to beneficially modulate tissue inflammation to promote healing. The present project proposal follows the hypothesis, that miR-10 represents an attractive, multifactual acting, new target to beneficially change the outcome post-MI in part by positively modulate angiogenesis, improving cardiomyocyte cell survival and controlling inflammatory processes. The proposed experiments aim at evaluating the therapeutic potential of cardiac miR-10 overexpression after MI. In the first specific aim I) we will evaluate the effects of miR-10 overexpression in vivo in control animals to assess potential adverse effects of a miR-10 therapy and we will collect initial data on parameters, including pharmacodynamics, pharmacokinetics and toxicology. In a second specific aim II) we will determine the beneficial impact of AAV9-miR-10 mediated overexpression in vivo post-MI. Therefor, we will assess changes in heart function and myocardial vascularization, in necrotic scar tissue distribution as well as cell death and accumulation of inflammatory cells under normal conditions and after MI. The conceptual design of this study follows a proof of concept approach in a non-clinical setting to systematically evaluate the potential of miR-10 therapy to treat ischemic heart disease.