Hydrogel-based delivery of antimiR-195 in a porcine model of myocardial infarction

Abstract Revascularization techniques have markedly improved patient survival after suffering a myocardial infarction (MI). However, the development of structural damage to the cardiac muscle post-MI persists. Consequently, stimulation of endogenous pathways that prompt cardiomyocyte (CM) proliferation has been explored to repopulate contractile muscle and reduce the post-ischemic burden. MicroRNA-195 (miR-195) is a post-transcriptional regulatory molecule involved in cell cycle repression and upregulated in infarcted myocardium, capable of stimulating CM proliferation in vivo when repressed with antisense oligonucleotides (ASO). To promote a local, sustained delivery to the heart, injectable slow-release hydrogels have been proposed to encapsulate ASOs. Here, we report the use of a supramolecular hydrogel composed of ureido-pyrimidinone (UPy) modified poly(ethylene glycol) (PEG) (UPy-PEG) and a UPy-functionalized recombinant human collagen type I peptide (RCPhC1) to deliver antimiR-195 to pig hearts. Right after MI induction, five sub-epicardial injections of either empty UPy-PEG-RCPhC1, antimiR-195 in saline or antimiR-195-laden UPy-PEG-RCPhC1 were administered. Twenty-eight days post-MI, cardiac function did not improve in neither of the antimiR-195-treated groups, though a non-significant scar size reduction was observed. Derepression of direct mRNA transcripts in infarcted tissue was observed, but microRNA-195 expression remained upregulated. Treatment with antimiR-195 also revealed an adverse myocardial remodeling, evidenced by increased microvascular resistance, CM size, and cardiac stress markers. Importantly, no notable recrudescence of arrhythmia was observed after antimiR-195 or UPy-PEG-RCPhC1. These data suggest the safe profile of UPy-PEG-RCPhC1 as an ASO carrier, but further dosing of antimiR-195 and release studies are needed before its clinical translation.