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Clinically relevant dosing of miR-145 micelles curbs atherosclerosis in vivo
Isabella Suzuki1, Anisa Ashraf1, Neil Patel1
1Department of Biomedical Engineering, University of Southern California, Los Angeles, CA, 90089, United States.
Insights
MicroRNA-145 (miR-145) micelles show promise as a cardiovascular disease therapy. This novel RNA therapy is stable, non-toxic, and effective in reducing atherosclerosis plaque growth and LDL cholesterol.
Area of Science:
- Cardiovascular Science
- RNA Therapeutics
- Biomedical Engineering
Background:
- Cardiovascular disease (CVD) is a leading global cause of death, primarily driven by atherosclerosis.
- Current LDL-lowering therapies like statins and PCSK9 inhibitors do not fully mitigate cardiovascular event risk for all patients.
- Targeting cellular phenotypes within atherosclerotic plaques offers a promising alternative therapeutic strategy.
Purpose of the Study:
- To evaluate the therapeutic efficacy of microRNA-145 (miR-145) incorporated into peptide amphiphile micelles using a clinically relevant dosing schedule.
- To assess the safety, stability, and comparative effectiveness of miR-145 micelles against existing treatments for atherosclerosis.
Main Methods:
- Developed miR-145 micelles targeting CC chemokine receptor 2 (CCR2) on vascular smooth muscle cells (VSMCs), endothelial cells (ECs), and macrophages.
- Administered miR-145 micelles to ApoE-/- mice every three weeks for 12 weeks, mimicking clinical RNA therapy schedules.
- Assessed plaque growth, weight gain, LDL cholesterol levels, cellular composition of plaques, and performed toxicity and stability analyses.
Main Results:
- miR-145 micelles significantly reduced plaque growth, weight gain, and circulating LDL cholesterol.
- The micelles stabilized plaques by decreasing pathogenic VSMCs, ECs, and macrophages.
- Compared to statins, miR-145 micelles demonstrated superior inhibition of pro-inflammatory cells and comparable LDL reduction, with no observed toxicity or immunogenicity.
- miR-145 micelles exhibited long-term stability at 4°C for up to one year, maintaining therapeutic function.
Conclusions:
- miR-145 micelles represent a practical and effective RNA-based therapeutic strategy for cardiovascular disease.
- The study validates a clinically feasible dosing regimen and demonstrates favorable safety and stability profiles for miR-145 micelles.
- These findings support the further development of miR-145 micelles as a novel treatment for atherosclerosis and associated cardiovascular events.
Abstract:
Cardiovascular disease (CVD) is the leading cause of death worldwide. Atherosclerosis or plaque buildup in the arterial walls is the most common cause of CVD. For atherosclerosis, statins and PCSK9 inhibitors are prescribed to patients to lower circulating low-density lipoprotein (LDL) cholesterol. However, lowering LDL does not reduce the risk of cardiovascular events, such as myocardial infarction (MI) and stroke, for all patients. Targeting phenotypic switching of plaque-resident cells offers an alternative therapeutic strategy. To that end, we previously showed microRNA-145 (miR-145) incorporated into monocyte chemoattractant protein 1 (MCP-1) peptide amphiphile micelles bind CC chemokine receptor 2 (CCR2) that is upregulated in synthetic vascular smooth muscle cells (VSMC) and activated endothelial cells (ECs) during atherosclerosis. Previously, miR-145 micelles delivered in murine ApoE-/- models of early and mid-stage atherosclerosis showed therapeutic promise when administered at frequent intervals (one injection every three days for 15 days), common to preclinical studies. However, to evaluate the therapeutic feasibility using a dosing schedule that is practical in the clinic, herein, we evaluated the therapeutic efficacy of miR-145 micelles dosed every three weeks (four injections over 12 weeks), matching a schedule similar to FDA-approved RNA therapies. We found that miR-145 micelles reduced plaque growth in the descending aorta, reduced weight gain, lowered circulating LDL, and stabilized plaque by reducing pathogenic cell populations of VSMCs, ECs, and macrophages. Moreover, when compared to statins, miR-145 micelles inhibited pro-inflammatory VSMCs, ECs, and macrophages to a greater degree and reduced serum LDL to a similar effect. Importantly, miR-145 micelles showed no signs of toxicity or immunogenicity upon histological, immunoglobulin, and liver function analyses. Lastly, miR-145 micelles stored up to one year in 4 °C showed long-term stability and sustained therapeutic function in vitro without the need for ultra-low temperatures common in RNA therapeutic storage. These findings demonstrate miR-145 micelles are practical as an RNA-based therapy and provide feasibility of their development as a treatment for cardiovascular disease.
