Novel Recombinant Biologics for the Treatment of Acute Coronary Syndromes and Infarction

Ischemia-reperfusion (IR) injury and myocardial infarction (MI) are all too common events following an acute coronary syndrome and often lead to adverse LV remodeling and heart failure (HF). While multifactorial, one contributory factor that accelerates adverse LV remodeling is an imbalance in matrix metalloproteinase (MMP) activation and the endogenous tissue inhibitors of MMPs (TIMPs). Accordingly, recombinant TIMPs are undergoing evaluation in terms of structure, delivery approaches, and timing for the purposes of interrupting post-MI remodeling. For the purposes of this presentation, delivery of recombinant TIMP-3 (rTIMP-3) will be described in terms of localized delivery, structural permutations, and finally intracoronary approaches relevant to the clinical context. The use of a novel, degradable hyaluronic acid hydrogel containing rTIMP-3 in a large animal MI model will be reviewed and advances in the use of MMP sensitive hydrogels will be discussed. Next, the biological effects of specific domains within the TIMP-3 molecule will be addressed through examining the effects of myocardial injections of either a full length recombinant TIMP-3 (F-TIMP-3) or a truncated form encompassing the N-terminal region (N-TIMP-3) on indices of post-MI remodeling. Finally, whether and to what degree intracoronary delivery of rTIMP-3 post-IR is feasible and effective will be examined. This presentation will identify that recombinant biologics can be locally delivered, reduce systemic side effects, and provide significant therapeutic effects on post-MI remodeling.