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Single-Dose Intracardiac Injection of Pro-Regenerative MicroRNAs Improves Cardiac Function After Myocardial
Pierluigi Lesizza1, Giulia Prosdocimo1, Valentina Martinelli1
1From the Molecular Medicine (P.L., G.P., V.M., M.G.) and Cardiovascular Biology (S.Z.) Laboratories, International Centre for Genetic Engineering and Biotechnology (ICGEB), Trieste, Italy; and Department of Medical, Surgical and Health Sciences, University of Trieste, Italy (P.L., G.S., S.Z., M.G.).
Rationale:
Recent evidence indicates that a few human microRNAs (miRNAs), in particular hsa-miR-199a-3p and hsa-miR-590-3p, stimulate proliferation of cardiomyocytes and, once expressed in the mouse heart using viral vectors, induce cardiac regeneration after myocardial infarction. Viral vectors, however, are not devoid of safety issues and, more notably, drive expression of the encoded miRNAs for indefinite periods of time, which might not be desirable in light of human therapeutic application.
Objective:
As an alternative to the use of viral vectors, we wanted to assess the efficacy of synthetic miRNA mimics in inducing myocardial repair after single intracardiac injection using synthetic lipid formulations.
Methods And Results:
We comparatively analyzed the efficacy of different lipid formulations in delivering hsa-miR-199a-3p and hsa-miR-590-3p both in primary neonatal mouse cardiomyocytes and in vivo. We established a transfection protocol allowing persistence of these 2 mimics for at least 12 days after a single intracardiac injection, with minimal dispersion to other organs and long-term preservation of miRNA functional activity, as assessed by monitoring the expression of 2 mRNA targets. Administration of this synthetic formulation immediately after myocardial infarction in mice resulted in marked reduction of infarct size and persistent recovery of cardiac function.
Conclusions:
A single administration of synthetic miRNA-lipid formulations is sufficient to stimulate cardiac repair and restoration of cardiac function.
Insights
Synthetic microRNA (miRNA) mimics delivered via lipid formulations promote cardiac repair after heart attack. A single injection effectively regenerated heart tissue and restored function, offering a safer alternative to viral vectors for myocardial infarction treatment.
Area of Science:
- Cardiovascular Biology
- Regenerative Medicine
- Molecular Therapy
Background:
- Human microRNAs (miRNAs), specifically hsa-miR-199a-3p and hsa-miR-590-3p, have shown potential in stimulating cardiomyocyte proliferation and cardiac regeneration.
- Viral vectors used for miRNA delivery pose safety concerns, including long-term, potentially undesirable expression, limiting their therapeutic application.
Purpose of the Study:
- To evaluate the efficacy of synthetic miRNA mimics encapsulated in lipid formulations for myocardial repair.
- To assess this approach as a safer alternative to viral vectors for treating myocardial infarction.
Main Methods:
- Comparative analysis of lipid formulations for delivering hsa-miR-199a-3p and hsa-miR-590-3p in neonatal mouse cardiomyocytes and in vivo.
- Development of an intracardiac injection protocol for sustained miRNA mimic persistence (≥12 days) with minimal off-target effects.
- Assessment of miRNA functional activity through monitoring mRNA target expression.
Main Results:
- A single intracardiac injection of synthetic miRNA mimics in lipid formulations led to sustained miRNA activity.
- The treatment significantly reduced infarct size in mice post-myocardial infarction.
- Restoration of cardiac function was observed with persistent recovery.
Conclusions:
- Synthetic miRNA-lipid formulations enable effective cardiac repair and functional recovery after a single administration.
- This approach presents a promising, safer therapeutic strategy for myocardial regeneration compared to viral vectors.
