Prompt coronary revascularization after a heart attack has significantly improved the outcome of myocardial infarction, but also have resulted in a growing number of survived patients with permanent damage of the heart, which frequently leads to heart failure. This condition is now common, expensive and lethal.
Over the past years, we had identified a method to stimulate regeneration of the cardiac muscle by promoting proliferation of the survived cardiomyocytes. This method entails the administration of a human microRNAs (miR-199a-3p) that reactivates division of these cells and re-muscularization of the damaged portion of the heart. NICE was a Proof-of-Concept project aimed to promote the translation of these findings towards clinical application.
First, we identified a proper formulation for miR-199a-3p delivery. Administration using a viral vector based on the adeno-associated virus (AAV) is effective, but it leads to permanent expression of the microRNA, which can eventually be undesired over time. Thus, we tested the possibility of delivering this microRNAs using lipid nanoparticles (LNPs) developed according to the Stable Nucleic Acid Lipid Particle (SNALP) technology. These are 80-100 nm particles carrying an RNA (same as some of the recent COVID-19 vaccines). We tested numerous formulation and lipids for specific cardiac delivery using a novel testing platform in mice, based on the parallel administration of LNPs carrying either the mRNA for a fluorescent protein or miR-199a-3p itself. Second, we tested the effect of different chemical modifications in the nucleotides forming miR-199a-3p. A proper set of these modifications now permits full efficacy of the miRNA and prolonged half life (over 10 days) once injected into the heart. With these modifications, we tested the effect of LNP-199 after myocardial infarction in mice. We found that a single administration is sufficient to induce marked cardiac remuscularization, which leads to stably improved cardiac function over time.
Finally, using our most effective formulation, we compared two routes of administration of LNP-199 in pigs, preliminary to human application. In particular, we tested direct intramyocardial injection (mimics administration during bypass surgery, or after a minithoracotomy, or upon transendocardial injection using left ventricular catheterization) or injection into the coronary artery after myocardial infarction (mimics administration after balloon angioplasty). Both routes scored effective in delivering the pro-regenerative LNP-199.
Based on these results, the project has spun out a start-up company that will lead the developed formulation towards a first-in-man clinical trial for cardiac regeneration.
