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In a Science Box session this morning, Doctor Daniele Catalucci (National Research Council-Institute of Genetic and Biomedical Research and Humanitas Research Hospital, Milan, Italy) will present results showing that a novel inhaled miR-133-loaded nanoparticle delivery approach can prevent cardiac dysfunction in an experimental model (Abstract 3072).
Non-coding micro-RNAs (miRNAs), like miR-133, are implicated in cardiovascular diseases and their downregulation within the myocardium has been observed in cardiac pathologies.1 Restoring levels may repair myocardial damage but effective delivery of exogenous miR-133 has been elusive. Inspired by the way that inhaled ultrafine pollution particles reach the heart via the circulation, Dr. Catalucci and his team began working with inhaled non-toxic, biodegradable nanoparticles as a way of directly targeting cardiomyocytes. Providing protection against RNase degradation, the calcium-phosphate nanoparticles (CaPs) are negatively charged so as to be attracted to polarised cells, such as cardiomyocytes.2 Once at the cells, the nanoparticles are internalised and release miR-133. This direct, non-invasive approach bypasses hepatic, renal and gastric degradation, meaning that relatively low doses of miR-133 would be required.
Dr. Catalucci and his team used the transaortic constriction (TAC) to induce ventricular pressure overload and heart failure in mice. TAC and non-TAC groups received either saline, CaP-miR-133, miR-133 alone or unloaded CaPs alone, delivered by intratracheal nebulisation on alternate days for four consecutive weeks. Echocardiographic analyses were performed at two and four weeks after surgery.
Notably, CaP-miR-133 led to reversal of heart failure progression, with preservation of left ventricular internal diameter, ejection fraction and fractional shortening, together with a reduction in myocardial fibrosis.
The improvement in cardiac function was associated with restoration of cardiomyocyte levels of miR-133.CaP-miR-133 administration was not associated with any major changes in immunological status. No beneficial effects were seen with miR-133 alone or unloaded CaPs alone. “This proof of concept has never been shown before for miRNAs and inhalation,” says Dr. Catalucci. “This important work represents a European collaboration between academia and industry (CUPIDO project, www.cupidoproject.eu) and we are now in the process of scaling up production ready for evaluation in large-animal models, with the hope it might lead to a first-in-class investigation in humans.”
Don’t miss today!Myocardial delivery of therapeutic miR-133 via inhalable nanoparticles prevents the pathologic development in a model of ventricular pressure overloadHeart failure: from bench to bed08:30 – 10:00; Science Box 1 – Poster Area
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1. Di Mauro V, et al. Noncoding RNA Res 2018;3:12–19.
2. Di Mauro V, et al. Nanomedicine (Lond) 2016;11:891–906.
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