mRNA Medicine for the Heart: From Vessel Growth After Heart Attack to Genome Editing

In a review published in Theranostics, Chinese and international cardiologists summarized the current achievements and prospects for the use of modified mRNA therapy in cardiology. The mRNA platform allows for the rapid production of targeted proteins directly in the desired tissues without the risk of integration into the genome, making it an ideal tool for myocardial regeneration, lowering cholesterol, combating fibrosis, and even genome editing.

1. Recovery after a heart attack

• mRNA-VEGF-A: Direct administration of LNP-packaged mRNA encoding vascular endothelial growth factor A into the infarct zone in mice and pigs induced significant angiogenesis (growth of new capillaries) and improved myocardial perfusion within 7–14 days.
• Reduction of infarct mass: Cardiomyocytes around the scar showed reduced apoptosis and increased proliferation, resulting in a 30–40% reduction in infarct area compared to controls.

2. Combating atherosclerosis and hypercholesterolemia

• mRNA-PCSK9 inhibitors: Use of LNP-delivered mRNAs producing small antibodies or single-chain antibody fragments against PCSK9 reduced plasma PCSK9 by >85% and LDL-cholesterol by 60–70% in preclinical models.
• Advantages over monoclonals: A single administration of the mRNA formula maintained the effect for more than 4 weeks and eliminated the need for expensive injections every 2-4 weeks.

3. Treatment and prevention of heart failure

• Anti-fibrotic mRNA: LNP-mRNA-FAP (fibroblastic active protein) in myocardial infarction mouse models suppressed cardiac fibroblast activation, slowing down scar tissue formation.
• mRNA-microRNA (miR-499): mRNA encoding miR-499 reduced cardiomyocyte apoptosis and activated oxidative phosphorylation pathways, which significantly improved cardiac contractility and animal survival.

4. Genomic editing for long-term correction

• VERVE-101: This is an LNP-packaged CRISPR/Cas base (adenine editor) against PCSK9 in the liver. In preclinical primates, a single infusion resulted in >90% PCSK9 gene editing and 70% reduction in LDL cholesterol, with effects lasting at least 6 months.
• Safety: No significant off-target mutations or systemic toxic reactions were observed, indicating greater accuracy of base-editing mRNA formulas.

Technical subtleties

• mRNA optimization: Use of pseudouridine and acetyl-5-methylcytidine increases stability and reduces immunogenicity; tailoring of 5'-caps and UTR enhances translation.
• Carriers: Lipid nanoparticles with an optimal ratio of ionic lipids, phospholipids and PEG lipids provide high delivery efficiency to cardiomyocytes or liver.
• Controlling the dose and timing of expression: mRNA drugs produce a “burst” of expression for 48–72 hours, after which protein levels quickly fall, reducing the risks of long-term changes in cells.

Authors' comments

“mRNA therapy opens up a whole new level of precision and flexibility in cardiology, from reopening blood vessels to editing genes,” said Dr. Fanli Peng, senior author of the review.

“The main challenges are ensuring sustainable and safe delivery of repeat doses, as well as scaling up production to GMP standards,” adds co-author Prof. Yun Zhang.

Prospects for clinical translation

• Clinical trials: Phase I/II trials are already planned for mRNA-VEGF-A in refractory heart failure and for LNP-mRNA-PCSK9 in hypercholesterolemia.
• Combination strategies: Possibility to combine mRNA therapy with traditional small molecule drugs or stem cells for synergistic effects.
• Personalized Medicine: Rapidly Tailoring mRNA Coding Sequences to Individual Patient Genetic Profiles.

The MRNA platform promises to become a universal “constructor” in cardiology, allowing the same basic technologies to solve a wide range of cardiovascular diseases - from angiogenesis to regulated genomic editing.