Self-Replicating Cell-Selective Therapy for Atherosclerotic Cardiovascular Disease

Advantages:

It utilizes a targeted approach by selectively expressing the therapeutic agent in vascular smooth muscle cells and infiltrating immune cells, it minimizes potential off-target effects and preserves the function of the endothelial cells.
By combining two complementary mechanisms, the miRNA switch and siRNA technology, this research addresses and tackles both cellular proliferation and inflammation, two key factors involved in atherosclerosis progression.
The use of mRNA as a therapeutic agent offers advantages such as high specificity and transient expression. The researchers leverage advanced techniques, including a miRNA switch and a siRNA-containing mRNA construct, to achieve targeted gene expression and inhibition.

Summary:

Current pharmacological interventions for atherosclerotic cardiovascular disease primarily focus on risk mitigation but fall short of directly addressing underlying plaque-forming cells. While the common therapy approach has been to treat the inflammation observed in atherosclerotic cardiovascular disease, site- and cell-selective therapies that target the atherosclerotic plaques, but not the endothelium are currently not available.

Our researchers have developed a cell-selective therapy for atherosclerotic plaques, targeting the cells responsible for their formation while protecting the endothelium. To achieve this, they employed a self-replicating miRNA switch approach. The miRNA switch consists of a synthetic mRNA encoding the cell cycle inhibitor p27 with a complementary target site for the endothelial cell (EC)-specific miR-126. This allows for the selective expression of p27 in VSMCs and infiltrating immune cells, while protecting the endothelium. Using a cationic amphipathic cell-penetrating peptide as a delivery platform, the mRNA self-assembles with the p27 miRNA switch into compacted nanoparticles.

This targeted approach offers a therapeutic solution for various stenotic conditions, potentially reducing the need for stents. Its customization ability to selectively target cells in diverse diseases, including fibrotic conditions, and enable cell-specific gene editing represents a significant stride toward precision medicine.