Abstract 4362971: Localized hydrogel delivery of a small molecule inhibitor of fibroblast activation protein alters the trajectory of post-myocardial infarction remodeling

Abstract

Background: Increased fibroblast activation protein (FAP) has been identified to occur within the myocardial infarction (MI) region in both patient and animal studies and has been implicated to contribute to the development and progression of heart failure with reduced ejection fraction (HFrEF). While small molecule FAP inhibitors, such as talabostat have been developed, systemic delivery has been problematic. We have developed a self-assembling hydrogel (SAgel) which can encapsulate small molecule therapeutics and provide localized release into the targeted tissue. Accordingly, we tested the hypothesis that localized delivery of the SAgel containing talabostat into the newly formed MI would alter post-MI remodeling and progression to HFrEF. Methods and Results: MI was induced in pigs (n=15, ischemia/reperfusion, balloon occlusion of LAD) and at 3-5 days post-MI, pigs were randomized to MI-SAGel/talabostat injections (n= 7) total payload of 30ug/mL) or (MI only; n=8). The MI injections (9 point array, 100 uL/injection, 3.33 ug/100 uL of talabostat) were performed through a minimally invasive mini-thoracotomy. The total payload of talabostat and release kinetic modeling yielded a daily effective localized concentration of approximately 10X the IC 50 . LV echocardiography performed at baseline (pre-MI) and at 28 days-post MI identified an improved LV ejection fraction, reduced LV dilation and lower pulmonary capillary wedge pressure, suggesting an attenuation in the progression of HFrEF in the SAgel/talabostat group. MI size by planimetry was reduced at 28 days post-MI in the SAgel/talabostat indicative of a reduction in MI expansion. Finally, FAP mRNA levels (rtPCR) were reduced within the MI region by over 70% from MI only values (p<0.001). Conclusions: This is the first study to demonstrate the feasibility and efficacy of targeted delivery of a self-assembling hydrogel containing a small molecule FAP inhibitor, using a minimally invasive cardiothoracic surgical approach at a relevant post-MI time point. This strategy may provide a platform for repurposing small molecule inhibitors for localized delivery to the LV myocardium.