Single Intracoronary Injection of Encapsulated Antagomir‐92a Promotes Angiogenesis and Prevents Adverse Infarct Remodeling

Abstract

BackgroundSmall and large preclinical animal models have shown that antagomir‐92a‐based therapy reduces early postischemic loss of function, but its effect on postinfarction remodeling is not known. In addition, the reported remote miR‐92a inhibition in noncardiac organs prevents the translation of nonvectorized miR‐targeted therapy to the clinical setting. We investigated whether a single intracoronary administration of antagomir‐92a encapsulated in microspheres could prevent deleterious remodeling of myocardium 1 month after acute myocardial infarction AUTHOR: Should “acute” be added before “myocardial infarction” (since abbreviation is AMI)? Also check at first mention in main text (AMI) without adverse effects.Methods and ResultsIn a percutaneous pig model of reperfused AMI, a single intracoronary administration of antagomir‐92a encapsulated in specific microspheres (9 μm poly‐d,‐lactide‐co‐glycolide [PLGA]) inhibited miR‐92a in a local, selective, and sustained manner (n=3 pigs euthanized 1, 3, and 10 days after treatment; 8×, 2×, and 5×‐fold inhibition at 1, 3, and 10 days). Downregulation of miR‐92a resulted in significant vessel growth (n=27 adult minipigs randomly allocated to blind receive encapsulated antagomir‐92a, encapsulated placebo, or saline [n=8, 9, 9]; P=0.001), reduced regional wall‐motion dysfunction (P=0.03), and prevented adverse remodeling in the infarct area 1 month after injury (P=0.03). Intracoronary injection of microspheres had no significant adverse effect in downstream myocardium in healthy pigs (n=2), and fluorescein isothiocyanate albumin‐PLGA microspheres were not found in myocardium outside the left anterior descending coronary artery territory (n=4) or in other organs (n=2).ConclusionsEarly single intracoronary administration of encapsulated antagomir‐92a in an adult pig model of reperfused AMI prevents left ventricular remodeling with no local or distant adverse effects, emerging as a promising therapeutic approach to translate to patients who suffer a large AMI.

Regulatory non‐coding RNAs in acute myocardial infarction

“…Bellera et al . demonstrated that a single intracoronary administration of antagomiR‐92a encapsulated in specific microspheres inhibited miR‐92a, resulting in significant vessel growth in a local, selective and sustained manner in a pig model of AMI. Bonauer et al .…”

An Emerging Role for isomiRs and the microRNA Epitranscriptome in Neovascularization

“…Inhibition of miR-92a increased angiogenesis in vivo and improved blood flow recovery after hindlimb ischemia [42]. Furthermore, administration of miR-92a inhibitors in porcine models for myocardial infarction demonstrated that miR-92 inhibition prevents adverse infarct remodeling and ischemia/reperfusion injury [43,44]. Phase 1 trials aimed to improve wound healing with a future potential clinical application towards heart failure treatment have recently been completed for miR-92a inhibitor MRG 110 (NCT03603431) [45].…”

RNA Therapeutics for Treatment of Cardiovascular Diseases

“…Intracoronary administration of antagomiR-92a encapsulated in specific microspheres (9 μm poly-d,-lactide-co-glycolide) was shown to preferentially target the vasculature and augment cardiac function in pigs. 10 But specific strategies for enriched delivery of ASO to the cardiovascular system are sparse. In contrast, for targeting the liver, nanoparticle containing ionizable amino lipids have become the leading delivery technology for siRNA, with several products in clinical trials.…”