Coronary heart disease is the single largest killer of men and women in the United States, yet ischemic effects can often be reversed by restoring coronary blood flow. Angiogenic factors offer the potential to reverse ischemia with minimal invasiveness, yet no angiogenic factors are currently approved. The thrombin peptide, TP508, accelerates repair of normal and ischemic dermal wounds and bone fractures through a mechanism that involves increased revascularization. It is currently being tested in both dermal and orthopedic US clinical trials. Preclinical experiments in which TP508 was injected into myocardium with induced ischemia showed increased angiogenesis and less ischemia in rabbit hearts and partially restored myocardial function in pig hearts. TP508 may therefore have significant benefit in restoring function to ischemic myocardium. Porcine heart models are more physiologically akin to humans than rabbits, but become prohibitively expensive for optimizing drug delivery. Therefore, in Phase I studies we will use the chick chorioallantoic membrane assay to determine appropriate delivery vehicle characteristics and use enhanced contrast magnetic resonance imaging of ischemic rabbit hearts to assess effects of TP508 preparations on myocardial perfusion. These studies will allow us to initiate Phase II product formulation and large animal validation studies.
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